3-Oxa phenyl-substituted PGE compounds

ABSTRACT

This invention is a group of 3-oxa and 4-oxa phenyl-substituted PGE type, PGF type, PGA type and PGB type compounds, and processes for making those. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of my copending application Ser. No.185,448, filed Sept. 30, 1971, now abandoned, which was acontinuation-in-part of my copending application Ser. No. 103,338 filedDec. 31, 1970, and now abandoned.

DESCRIPTION OF THE INVENTION

This invention relates to compositions of matter, and to methods andintermediates for producing them. In particular, the several aspects ofthis invention relate to novel analogs of some of the knownprostaglandins, for example, prostaglandin E₁ (PGE₁), prostaglandin E₂(PGE₂), prostaglandin F₁ (PGF₁.sub.α and PGF₁ .sub.β), prostaglandin F₂(PGF₂ .sub.α and PGF₂.sub.β), prostaglandin A₁ (PGA₁), prostaglandin A₂(PGA₂), prostaglandin B₁ (PGB₁), prostaglandin B₂ (PGB₂), and thedihydro derivatives of PGE₁, PGF₁ .sub.α, PGF₁ .sub.β, PGA₁, and PGB₁,to novel methods for producing those novel prostaglandin analogs, and tonovel chemical intermediates useful in those novel methods.

Each of the above-mentioned known prostaglandins is a derivative ofprostanoic acid which has the following structure and atom numbering:##SPC1##

A systematic name for prostanoic acid is7-[(2β-octyl)-cyclopent-1α-yl]heptanoic acid.

PGE₁ has the following structure: ##SPC2##

PGF₁ .sub.α has the following structure: ##SPC3##

PGF₁.sub.β has the following structure: ##SPC4##

PGA₁ has the following structure: ##SPC5##

PGB₁ has the following structure: ##SPC6##

Each of the known prostaglandins PGE₂, PGF₂.sub.α, PGF₂.sub.β, PGA₂, andPGB₂ has a structure the same as that shown for the corresponding PG₁compound except that in each, C-5 and C-6 are linked with a ciscarbon-carbon double bond. For example, PGE₂ has the followingstructure: ##SPC7##

Each dihydro derivative of PGE₁, PGF₁ .sub.α , PGF₁ .sub.β, PGA₁, andPGB₁ has a structure the same as that shown for the corresponding PG₁compound except that in each, C-13 and C-14 are linked with acarbon-carbon single bond. For example, dihydro-PGE₁ has the followingstructure. ##SPC8##

The prostaglandin formulas mentioned above each have several centers ofasymmetry. Each formula represents a molecule of the particularoptically active form of the prostaglandin obtained from certainmammalian tissues, for example, sheep vesicular glands, swine lung, andhuman seminal plasma, or by reduction or dehydration of a prostaglandinso obtained. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1(1968), and references cited therein. The mirror image of each formularepresents a molecule of the other enantiomeric form of thatprostaglandin. The racemic form of the prostaglandin consists of equalnumbers of two types of molecules, one represented by one of the aboveformulas and the other represented by the mirror image of that formula.Thus, both formulas are needed to define a racemic prostaglandin. SeeNature 212, 38 (1966) for discussion of the stereochemistry of theprostaglandins.

In formulas I, II, III, IV, V and VI, as well as in the formulas givenhereinafter, broken line attachments to the cyclopentane ring indicatesubstituents in alpha configuration, i.e., below the plane of thecyclopentane ring. Heavy solid line attachments to the cyclopentane ringindicate substituents in beta configuration, i.e., above the plane ofthe cyclopentane ring.

Prostaglandins with carboxyl-terminated side chains attached to thecyclopentane ring in beta configuration are also known. These arederivatives of 8-iso-prostanoic acid which has the following formula:##SPC9##

A systematic name for 8-iso-prostanoic acid is7-[(2β-octyl)-cyclopent-1β-yl]heptanoic acid.

The novel prostaglandin analogs of this invention each have an oxaoxygen (--O--) in place of the methylene (--CH₂ --) moiety at the3-position or at the 4-position of the prostanoic acid structure (I) orthe 8-iso-prostanoic acid structure (VII). The novel prostaglandinanalogs of this invention also each have a benzene ring as part of theC-13 to C-20 chain of the prostanoic acid or 8-iso-prostanoic acidstructure. That benzene ring is present as a substituted orunsubstituted phenyl moiety attached as a substituent to one of themethylenes between C-15 and the terminal methyl of the prostanoic acidor 8-iso-prostanoic acid structure. Alternatively, the substituted orunsubstituted phenyl moiety is attached to the terminal or omega carbonof the C-16 to C-20 portion of the chain, replacing one of the hydrogensof the terminal methyl, the entire terminal methyl, or the terminalmethyl plus one to four of the methylenes adjacent to that terminalmethyl. For example, three of the novel prostaglandin analogs of thisinvention are represented by the formulas: ##SPC10##

Based upon its relationship to PGE₁ and prostanoic acid, the compound offormula VIII is named 4-oxa-19-phenyl-PGE₁. Similarly, the compound offormula IX is named 3-oxa-17-phenyl-18,19,20-trinor-PGE₁, and thecompound of formula X is named 3-oxa-18-phenyl-19,20-dinor-PGF₂ .sub.α.In those names, 3-oxa and 4-oxa indicate an oxa oxygen (--O--) in placeof the 3-methylene and 4-methylene, respectively, of PGE₁. Also, informulas IX and X, trinor and dinor indicate absence of the terminal--CH₂ --CH₂ --CH₃ and the terminal --CH₂ --CH₃, respectively, of PGE₁and PGF₂ .sub.α. The words nor, dinor, trinor, tetranor, and pentanor inthe names given here and hereinafter for novel prostaglandins of thisinvention are to be construed as indicating the number of carbon atomsmissing from the C-16 to C-20 position of the prostanoic acid carbonskeleton. The phenyl or substituted phenyl moiety is attached to theremaining portion of the prostanoic acid skeleton, i.e., to C-19 for thenor-compounds, to C-18 for the dinor compounds, to C-17 for the trinorcompounds, to C-16 for the tetranor compounds and to C-15 for thepentanor compounds.

Some of the novel prostaglandin analogs of this invention differstructurally in other ways from the known prostanoic acid derivatives,having for example, more or fewer carbon atoms in the C-1 to C-7 chainof prostanoic acid, and having one or more alkyl and/or fluorosubstituents in that chain or in the C-13 to C-20 chain of prostanoicacid.

The following formulas represent the novel 3-oxa and 4-oxaphenyl-substituted prostaglandin analogs of this invention: ##SPC11##

Formulas XI to XVIII represent 3-oxa and 4-oxa phenyl-substitutedcompounds of the PGE type. Formulas XIX to XXVI represent 3-oxa and4-oxa phenyl-substituted compound of the PGF type. Formulas XXVII toXXXIV represent 3-oxa and 4-oxa phenyl-substituted compounds of the PGAtype. Formulas XXXV to XLII represent 3-oxa and 4-oxa phenyl-substitutedcompounds of the PGB type.

In formulas XI to XLII, R₁ is hydrogen, alkyl of one to 8 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one to 3chloro or alkyl of one to 4 carbon atoms, inclusive, or ethylsubstituted in the β-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3iodo. R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are hydrogen or alkyl of one to 4carbon atoms, inclusive. The divalent moiety --C_(n) H_(2n) --represents alkylene of one to 10 carbon atoms, inclusive, with one to 5carbon atoms, inclusive, between --CHR₂ -- and --O--. The divalentmoiety --C_(m) H_(2m) -- represents alkylene of 1 to 9 carbon atoms,inclusive, with 1 to 4 carbon atoms, inclusive, between --CHR₂ -- and--O--. The divalent moiety --C_(p) H_(2p) -- represents alkylene of oneto 8 carbon atoms, inclusive, with one, 2, or 3 carbon atoms between--CH=CH-- or --C.tbd.C-- and --O--. The divalent moiety --C_(q) H_(2q)-- represents alkylene of one to 7 carbon atoms, inclusive, with 1 or 2carbon atoms between --CH=CH-- or --C.tbd.C-- and --O--. The moiety--C_(t) H_(2t) -- represents a valence bond, i.e., wherein t is zero, oralkylene of one to 10 carbon atoms, inclusive, i.e., wherein t is one to10, substituted with zero, one, or 2 fluoro, with one to 7 carbon atoms,inclusive, between --CR₃ OH-- and the ring. When one or 2 fluoro arepresent as substituents of --C_(t) H_(2t) --, that moiety will contain2t- 1 or 2t-2 hydrogen atoms, respectively, rather than 2t hydrogenatoms. The symbol T represents alkyl of one to 4 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or --OR₉, wherein R₉ ishydrogen, alkyl of one to 4 carbon atoms inclusive, ortetrahydropyranyl. The symbol s represents zero, one, 2 or 3. Regardingthe combination (T)_(s) attached to the phenyl ring, no more than two Tare other than alkyl. Except for that proviso, when two or three T arepresent as substituents, they are the same or different.

The wavy line ˜ in formulas XI to XXXIV indicates attachment of thegroup to the ring in alpha or beta configuration. In the case of thecompounds of formulas XIX to XXVI, there are two wavy lines, and thoseformulas encompass compounds wherein the configurations of the hydroxyand the carboxyl-terminated moieties are, respectively, α,α, α,β, β,α,and β,β.

Formulas XI to XLII include lower alkanoates, and also pharmacologicallyacceptable salts when R₁ is hydrogen.

Also included in Formulas XI to XLII are separate isomers wherein theside chain hydroxy is in S or R (epi) configuration.

Included in Formulas XIII, XIV, XXI, XXII, XXIX, XXX, XXXVII, andXXXVIII are both the cis and the trans compounds with respect to thecarbon-carbon double bond in the carboxy-terminated side chain. In allof the compounds containing --CH=CR₄ --, that carbon-carbon double bondis in trans configuration, and the chain containing R₄ is attached tothe cyclopentane ring in beta configuration in compounds encompassed byFormulas XI to XXXIV.

The novel 3-oxa and 4-oxa phenyl-substituted prostaglandin analogs ofthis invention include racemic compounds and both optically activeenantiomeric forms thereof. As discussed hereinabove, two structuralformulas are required to define accurately these racemic compounds. Forconvenience, only a single structural formula is used, for example,Formulas XI to XLII, to define the racemic form and both enantiomericforms of each group of novel prostaglandin analogs. Each formula is,however, to be construed as including said racemic forms and both ofsaid optically active enantiomeric forms.

Formula XI represents 3-oxa-17-phenyl-18,19,20-trinor-PGE₁ (Formula IXhereinabove) when R₁, R₂, R₃, R₄, R₅, and R₆ are each hydrogen, C_(n)H_(2n) is trimethylene (n is 3), C_(t) H_(2t) is ethylene (t is 2), s iszero, the carboxyl-terminated side chain is attached to the cyclopentanering in alpha configuration, and the configuration of the side chainhydroxy is S.

With regard to Formulas XI to XLII, examples of alkyl of one to 4 carbonatoms, inclusive, are methyl, ethyl, propyl, butyl, and isomeric formsthereof. Examples of alkyl of one to 8 carbon atoms, inclusive, arethose given above, and pentyl, hexyl, heptyl, octyl, and isomeric formsthereof. Examples of alkyl of one to 10 carbon atoms, inclusive, arethose given above, and nonyl, decyl, and isomeric forms thereof.Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, whichincludes alkyl-substituted cycloalkyl, are cyclopropyl,2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkylof 7 to 12carbon atoms, inclusive, are benzyl, phenethyl, 1-phenylethyl,2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(1-naphthylethyl), and1-(2-naphthylmethyl). Examples of phenyl substituted by one to 3 chloroor alkyl of one to 4 carbon atoms, inclusive, are p-chlorophenyl,m-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl,2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl,p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl, and2,4-dichloro-3-methylphenyl.

Examples of alkylene within the scope of --C_(n) H_(2n) --, --C_(m)H_(2m) --, --C_(p) H_(2p) --, and --C_(q) H_(2q) -- as defined above,are methylene, ethylene, trimethylene, tetramethylene, pentamethylene,and those alkylene with one or more alkyl substituents on one or morecarbon atoms thereof, e.g., --CH(CH₃)--, --C(CH₃)₂ --, --CH(CH₂ CH₃)--,--CH₂ --CH(CH₃)--, --CH(CH₃)--CH(CH₃)--, --CH₂ --C(CH₃)₂ --, --CH₂--CH(CH₃)--CH₂ --, --CH₂ --CH₂ --CH(CH₂ CH₃)--, and the like.

Examples of alkylene within the scope of --C_(t) H_(2t) -- as definedabove are those mentioned above, and also hexamethylene andheptamethylene, those with one or more alkyl substituents on one or morecarbon atoms thereof, e.g., --CH₂ --CH₂ --CH₂ --CH₂ --CH₂ CH(CH₃)--, and--CH(CH₃)--CH₂ --CH₂ --CH₂ --CH₂ --CH₂ --C(CH₃)₂ --, and also alkylenesubstituted with one or 2 fluoro, e.g., --CH₂ --CHF--CH₂ --, --CHF--CH₂--, --CHF--CHF--, --CHF--CH₂ --CH₂ --CH(CH₃)--, and --CHF--CH₂ --CH(CH₂CH₂ CH₃)--CH₂ --CH₂ --.

Examples of ##SPC12##

as defined above are phenyl, p-tolyl, m-tolyl, o-tolyl, p-fluorophenyl,m-fluorophenyl, o-fluorophenyl, p-chlorophenyl, m-chlorophenyl,o-chlorophenyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl,o-trifluoromethylphenyl, p-hydroxyphenyl, m-hydroxyphenyl,o-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl,p-tetrahydropyranyloxyphenyl, m-tetrahydropyranyloxyphenyl,o-tetrahydropyranyloxyphenyl, o-ethylphenyl, m-isopropylphenyl,p-tert-butylphenyl, p-butoxyphenyl, 3,4-dimethylphenyl,2,4-diethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl,2,4-dichlorophenyl, 3,4-difluorophenyl, 2-chloro-4-methylphenyl,2-fluoro-4-methoxyphenyl, 3,5-dimethyl-4-fluorophenyl,2,6-dimethyl-4-hydroxyphenyl, and 2,4-di(trifluoromethyl)phenyl.

PGE₁, PGE₂, dihydro-PGE₁, and the corresponding PGF.sub.α, PGF.sub.β,PGA, and PGB compounds, and their esters, acylates, andpharmacologically acceptable salts, are extremely potent in causingvarious biological responses. For that reason, these compounds areuseful for pharmacological purposes. See, for example, Bergstrom et al.,Pharmacol. Rev. 20, 1 (1968), and references cited therein. A few ofthose biological responses are systemic arterial blood pressure loweringin the case of the PGE, PGF.sub.β, and PGA compounds as measured, forexample, in anesthetized (pentobarbital sodium) pentolinium-treated ratswith indwelling aortic and right heart cannulas; pressor activity,similarly measured, for the PGF.sub.α compounds; stimulation of smoothmuscle as shown, for example, by tests on strips of guinea pig ileum,rabbit duodenum, or gerbil colon; potentiation of other smooth musclestimulants; antilipolytic activity as shown by antagonism ofepinephrine-induced mobilization of free fatty acids or inhibition ofthe spontaneous release of glycerol from isolated rat fat pads;inhibition of gastric secretion in the case of the PGE and PGA compoundsas shown in dogs with secretion stimulated by food or histamineinfusion; activity on the central nervous system; decrease of bloodplatelet adhesiveness as shown by platelet-to-glass adhesiveness, andinhibition of blood platelet aggregation and thrombus formation inducedby various physical stimuli, e.g., arterial injury, and variousbiochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen;and in the case of the PGE and PGB compounds, stimulation of epidermalproliferation and keratinization as shown when applied in culture toembryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 μg. to about10 mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE and PGA compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secretion, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 μg. to about 500 μg.per kg. of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.1 to about 20 mg. per kg. of bodyweight per day, the exact dose depending on the age, weight, andcondition of the patient or animal, and on the frequency and route ofadministration.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful whenever it isdesired to inhibit platelet aggregation, to reduce the adhesivecharacter of platelets, and to remove or prevent the formation ofthrombi in mammals, including man, rabbits, and rats. For example, thesecompounds are useful in the treatment and prevention of myocardialinfarcts, to treat and prevent post-operative thrombosis, to promotepatency of vascular grafts following surgery, and to treat conditionssuch as atherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE, PGF.sub.α, and PGF.sub.β compounds are especially useful asadditives to blood, blood products, blood substitutes, and other fluidswhich are used in artificial extracorporeal circulation and perfusion ofisolated body portions, e.g., limbs and organs, whether attached to theoriginal body, detached and being preserved or prepared for transplant,or attached to a new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, PGE₂, for example, is useful in place of or in combinationwith less than usual amounts of these known smooth muscle stimulators,for example, to relieve the symptoms of paralytic ileus, or to controlor prevent atonic uterine bleeding after abortion or delivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 μg. per kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.01 to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PGE, PGA, and PGF.sub.β compounds are useful as hypotensive agentsto reduce blood pressure in mammals, including man. For this purpose,the compounds are administered by intravenous infusion at the rate about0.01 to about 50 μg. per kg. of body weight per minute, or in single ormultiple doses of about 25 to 500 μg. per kg. of body weight total perday.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful in place ofoxytocin to induce labor in pregnant female animals, including man,cows, sheep, and pigs, at or near term, or in pregnant animals withintrauterine death of the fetus from about 20 weeks to term. For thispuprpose, the compound is infused intravenously at a dose of 0.01 to 50μg. per kg. of body weight per minute until or near the termination ofthe second stage of labor, i.e., expulsion of the fetus. These compoundsare especially useful when the female is one or more weeks post-matureand natural labor has not started, or 12 to 60 hours after the membraneshave ruptured and natural labor has not yet started. An alternativeroute of administration is oral.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful for controllingthe reproductive cycle in ovulating female mammals, including humans andanimals such as monkeys, rats, rabbits, dogs, cattle, and the like. Bythe term ovulating female mammals is meant animals which are matureenough to ovulate but not so old that regular ovulation has ceased. Forthat purpose PGF₂.sub.α, for example, is administered systemically at adose level in the range 0.01 mg. to about 20 mg. per kg. of body weightof the female mammal, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. Intravaginal and intrauterineare alternative routes of administration. Additionally, expulsion of anembryo or a fetus is accomplished by similar administration of thecompound during the first third of the normal mammalian gestationperiod.

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e.g., diabetes mellitus, vascular diseases, andhyperthyroidism.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal disfunction, especially in cases of severelyimpaired renal blood flow, for example, the hepatorenal syndrome andearly kidney transplant rejection. In cases of excessive orinappropriate ADH (antidiuretic hormone; vasopressin) secretion, thediuretic effect of these compounds is even greater. In anephric states,the vasopressin action of these compounds is especially useful.Illustratively, the PGA compounds are useful to alleviate and correctcases of edema resulting, for example, from massive surface burns, andin the management of shock. For these purposes, the PGA compounds arepreferably first administered by intravenous injection at a dose in therange of 10 to 1000 μg. per kg. of body weight or by intravenousinfusion at a dose in the range 0.1 to 20 μg. per kg. of body weight perminute until the desired effect is obtained. Subsequent doses are givenby intravenous, intramuscular, or subcutaneous injection or infusion inthe range 0.05 to 2 mg. per kg. of body weight per day.

The PGE and PGB compounds promote and accelerate the growth of epidermalcells and keratin in animals, including humans, useful domestic animals,pets, zoological specimens, and laboratory animals. For that reason,these compounds are useful to promote and accelerate healing of skinwhich has been damaged, for example, by burns, wounds, and abrasions,and after surgery. These compounds are also useful to promote andaccelerate adherence and growth of skin autografts, expecially small,deep (Davis) grafts which are intended to cover skinless areas bysubsequent outward growth rather than initially, and to retard rejectionof homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate, a wet dressing for topical application to second and/orthird degree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 1to 500 μg./ml. of the PGB compound or several times that concentrationof the PGE compound. Especially for topical use, these prostaglandinsare useful in combination with antibiotics, for example, gentamycin,neomycin, polymyxic B, bacitracin, spectinomycin, and oxytetracycline,with other antibacterials, for example, mafenide hydrochloride,sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoidsteroids, for example, hydrocortisone, prednisolone, methylprednisolone,and fluprednisolone, each of those being used in the combination at theusual concentration suitable for its use alone.

The novel Formula XI-to-XVIII 3-oxa and 4-oxa phenyl-substitutedPGE-type compounds, the novel Formula XIX-to-XXVI 3-oxa and 4-oxaphenyl-substituted PGF.sub.α- and PGF.sub.β-type compounds, the novelFormula XXVII-to-XXXIV 3-oxa and 4-oxa phenyl-substituted PGA-typecompounds, and the novel Formula XXXV-to-XLII 3-oxa and 4-oxaphenyl-substituted PGB-type compounds each cause the biologicalresponses described above for the PGE, PGF.sub.α, PGF.sub.β, PGA, andPGB compounds, respectively, and each of these novel compounds isaccordingly useful for the above-described corresponding purposes, andis used for those purposes in the same manner as described above.

The known PGE, PGF.sub.α, PGF.sub.β, PGA and PGB compounds are allpotent in causing multiple biological responses even at low doses. Forexample, PGE₁ and PGE₂ are extremely potent in causing vasodepressionand smooth muscle stimulation, and also are potent as antilipolyticagents. However, for many applications, these known prostaglandins havean inconveniently short duration of biological activity. In strikingcontrast, the novel prostaglandin analogs of Formulas XI to XLII aresubstantially more specific with regard to potency in causingprostaglandin-like biological responses, and have a substantially longerduration of biological activity. Therefore, each of these novelprostaglandin analogs is surprisingly and unexpectedly more useful thanone of the corresponding above-mentioned known prostaglandins for atleast one of the pharmacological purposes indicated above for thelatter. Use of the novel analog for that purpose results in smallerundesired side effects than when the known prostaglandin is used for thesame purpose. Moreover, because of its prolonged activity, fewer andsmaller doses of the novel prostaglandin analog can frequently be usedto attain the desired result.

To obtain the optimum combination of biological response specificity,potency, and duration of activity, certain compounds within the scope ofFormulas XI to XLII are preferred. For example, it is preferred that thecarboxy-terminated chain in each formula contain a chain of six atomsbetween the carboxy and the cyclopentane ring. One of those six atomswill be the oxa atom and the other five will be carbon atoms.Accordingly and with reference to formulas XI to XLII, it is preferredthat --C_(n) H_(2n) -- represent a 3-carbon divalent chain, that --C_(m)H_(2m) -- represent a 2-carbon divalent chain, and that --C_(p) H_(2p)-- represent a divalent carbon atom. These preferences do not excludeadditional carbon atoms (alkyl groups) as branching.

A seven-atom carboxy-terminated chain is not included in the compoundsof Formulas XIV, XVI, XXII, XXIV, XXX, XXXII, XXXVIII, XL, i.e.,formulas wherein the carboxy-terminated side chain is 4-oxa and containsa carbon-carbon double or triple bond. In each of those compounds, the qof --C_(q) H_(2q) is at least one; and at least seven atoms, one oxygen(oxa) and six carbons, are present between the carboxyl and thecyclopentane ring. Preferably, q is one.

Another preference for the compounds of Formulas XI to XLII is that R₂,R₃, R₄, R₅, R₆, R₇, and R₈ are hydrogen or methyl. All of those R groupscan be hydrogen, all can be methyl, or there can be any of the possiblecombinations of hydrogen and methyl. It is especially preferred that R₃be methyl.

Another preference for the compounds of Formulas XI to XLII is that--C_(t) H_(2t) be a valence bond, i.e., t is zero, or straight chainalkylene of one to 4 carbon atoms, i.e., --(CH₂)_(d) -- wherein d isone, 2, 3, or 4, with or without a fluoro or alkyl substituent on thecarbon adjacent to the hydroxy-substituted carbon (C-15 in PGE₁), e.g.,--CHF--(CH₂)_(g) --, --CH(CH₃)--(CH₂)_(g) --, --CH(C₂ H₅)--(CH₂)_(g) --,--C(CH₃)₂ --(CH₂)_(g) --, --C(C₂ H₅)₂ --(CH₂)_(g) --, --C(CH₃)(C₂H₅)--CH₂)_(g) --, wherein g is zero, one, 2, or 3. It is also preferredthat the phenyl ring, when substituted, i.e., s is not zero, besubstituted at least at the para position.

Another advantage of the novel compounds of this invention, especiallythe preferred compounds defined hereinabove, compared with the knownprostaglandins, is that these novel compounds are administeredeffectively orally, sublingually, intravaginally, buccally, or rectally,in addition to usual intravenous, intramuscular, or subcutaneousinjection or infusion methods indicated above for the uses of the knownprostaglandins. These qualities are advantageous because they facilitatemaintaining uniform levels of these compounds in the body with fewer,shorter, or smaller doses, and make possible self-administration by thepatient.

The 3-oxa and 4-oxa phenyl-substituted PGE, PGF.sub.α, PGF.sub.β, PGA,and PGB type compounds encompassed by Formula XI to XLII, including thespecial classes of compounds described above, are used for the purposesdescribed above in the free acid form, in ester form, or inpharmacologically acceptable salt form. When the ester form is used theester is any of those within the above definition of R₁. However, it ispreferred that the ester be alkyl of one to four carbon atoms,inclusive. Of those alkyl, methyl and ethyl are especially preferred foroptimum absorption of the compound by the body or experimental animalsystem.

Pharmacologically acceptable salts of these Formula XI-to-XLII compoundsuseful for the purposes described above are those with pharmacologicallyacceptable metal cations, ammonium, amine cations, or quaternaryammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, zinc, and iron, are within the scope of thisinvention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic,and araliphatic amines containing up to and including about 18 carbonatoms, as well as heterocyclic amines, e.g., piperidine, morpholine,pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g.,1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine,2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and thelike, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine,N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

The 3-oxa and 4-oxa phenyl-substituted PGE, PGF.sub.α, PGF.sub.β, PGA,and PGB type compounds encompassed by Formulas XI to XLII, including thespecial classes of compounds described above, are also used for thepurposes described above in free hydroxy form or in the form wherein thehydroxy moieties are transformed to lower alkanoate moieties, e.g., --OHto --OCOCH₃. Examples of lower alkanoate moieties are acetoxy,propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy,octanoyloxy, and branched chain alkanoyloxy isomers of those moieties.Especially preferred among these alkanoates for the above describedpurposes are the acetoxy compounds. These free hydroxy and alkanoyloxycompounds are used as free acids, as esters, and in salt form all asdescribed above.

As discussed above, the compounds of Formulas XI to XLII areadministered in various ways for various purposes; e.g., intravenously,intramuscularly, subcutaneously, orally, intravaginally, rectally,buccally, sublingually, topically, and in the form of sterile implantsfor prolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For that purpose, it is preferred because ofincreased water solubility that R₁ in the Formula XI-to-XLII compound behydrogen or a pharmacologically acceptable cation. For subcutaneous orintramuscular injection, sterile solutions or suspensions of the acid,salt, or ester form in aqueous or non-aqueous media are used. Tablets,capsules, and liquid preparations such as syrups, elixirs, and simplesolutions, with the usual pharmaceutical carriers are used for oral orsublingual administration. For rectal or vaginal administration,suppositories prepared as known in the art are used. For tissueimplants, a sterile tablet or silicone rubber capsule or other objectcontaining or impregnated with the substance is used.

The 3-oxa and 4-oxa phenyl-substituted PGE, PGF.sub.α, PGF.sub.β, PGA,and PGB compounds encompassed by Formulas XI to XLII are produced by thereactions and procedures described and exemplified hereinafter.

The various 3-oxa and 4-oxa phenyl-substituted PGF.sub.α-type andPGF.sub.β-type compounds encompassed by Formulas XIX to XXVI areprepared by carbonyl reduction of the corresponding PGE-type compoundsencompassed by Formulas XI to XVIII. For example, carbonyl reduction of3-oxa-17-phenyl-18,19,20-trinor-PGE₁ gives a mixture of3-oxa-17-phenyl-18,19,20-trinor-PGF₁ .sub.α and3-oxa-17-phenyl-18,19,20-trinor-PGF₁ .sub.β.

These ring carbonyl reductions are carried out by methods known in theart for ring carbonyl reductions of known prostanoic acid derivatives.See, for example, Bergstrom et al., Arkiv Kemi 19, 563 (1963), ActaChem. Scand. 16, 969 (1962), and British Specification No. 1,097,533.Any reducing agent is used which does not react with carbon-carbondouble bonds or ester groups. Preferred reagents are lithium(tri-tert-butoxy)aluminum hydride, the metal borohydrides, especiallysodium, potassium and zinc borohydrides, and the metal trialkoxyborohydrides, e.g., sodium trimethoxyborohydride or sodiumtriethoxyborohydride. The mixtures of alpha and beta hydroxy reductionproducts are separated into the individual alpha and beta isomers bymethods known in the art for the separation of analogous pairs of knownisomeric prostanoic acid derivatives. See, for example, Bergstrom etal., cited above, Granstrom et al., J. Biol. Chem. 240, 457 (1965), andGreen et al., J. Lipid Research 5, 117 (1964). Especially preferred asseparation methods are partition chromatographic procedures, both normaland reversed phase, preparative thin layer chromatography, andcountercurrent distribution procedures.

The various 3-oxa and 4-oxa phenyl-substituted PGA-type compoundsencompassed by Formulas XXVII to XXXIV are prepared by acidicdehydration of the corresponding PGE-type compounds encompassed byFormulas XI to XVIII. For example, acidic dehydration of3-oxa-17-phenyl-18,19,20-trinor-PGE₁ gives3-oxa-17-phenyl-18,19,20-trinor-PGA₁.

These acidic dehydrations are carried out by methods known in the artfor acidic dehydrations of known prostanoic acid derivatives. See, forexample, Pike et al., Proc. Nobel Symposium II, Stockholm (1966);Interscience Publishers, New York, pp. 162-163 (1967), and BritishSpecification No. 1,097,533. Alkanoic acids of 2 to 6 carbon atoms,inclusive, especially acetic acid, are preferred acids for this acidicdehydration. Dilute aqueous solutions of mineral acids, e.g.,hydrochloric acid, especially in the presence of a solubilizing diluent,e.g., tetrahydrofuran, are also useful as reagents for this acidicdehydration, although these reagents may also cause partial hydrolysisof an ester reactant.

The various 3-oxa and 4-oxa phenyl-subsituted PGB-type compoundsencompassed by Formulas XXXV to XLII are prepared by basic dehydrationof the corresponding PGE-type compounds encompassed by Formulas XI toXVIII, or by contacting the corresponding PGA-type compounds encompassedby Formulas XXVII to XXXIV with base. For example, both3-oxa-17-phenyl-18,19,20-trinor-PGE₁ and3-oxa-17-phenyl-18,19,20-trinor-PGA₁ give3-oxa-17-phenyl-18,19,20-trinor-PGB₁ on treatment with base.

These basic dehydrations and double bond migrations are carried out bymethods known in the art for similar reactions of known prostanoic acidderivatives. See, for example, Bergstrom et al., J. Biol. Chem. 238,3555(1963). The base is any whose aqueous solution has pH greater than 10.Preferred bases are the alkali metal hydroxides. A mixture of water andsufficient of a water-miscible alkanol to give a homogeneous reactionmixture is suitable as a reaction medium. The PGE type or PGA typecompound is maintained in such a reaction medium until no further PGBtype compound is formed, as shown by the characteristic ultravioletlight absorption near 278 mμ for the PGB type compound.

The various transformations of 3-oxa and 4-oxa phenyl-substitutedPGE-type compounds of Formulas XI to XVIII to the corresponding 3-oxaand 4-oxa-phenyl-substituted PGF.sub.α, PGF.sub.β, PGA, and PGB typecompounds are shown in Chart A, wherein R₁, R₂, R₃, and ˜ are as definedabove, wherein E is --CH₂ CHR₄ -- or trans --CH=CR₄ --, wherein V is--C_(n) H_(2n) --O--CR₅ R₆ --, --C_(m) H_(2m) --O--CR₅ R₆ --CR₇ R₈ --,--CH=CH--C_(p) H_(2p) --O--CR₅ R₆ -- (cis or trans), --CH=CH--C_(q)H_(2q) --O--CR₅ R₆ --CR₇ R₈ --(cis or trans), --C.tbd.C--C_(p) H_(2p)--O--CR₅ R₆ --, or --C.tbd.C--C_(q) H_(2q) --O--CR₅ R₆ --CR₇ R₈ --,wherein R₄, R₅, R₆, R₇ , R₈, n, m, p, and q are as defined above, withthe proviso that V is --C_(n) H_(2n) --O--CR₅ R₆ -- or --C_(m) H_(2m)--O--CR₅ R₆ --CR₇ R₈ -- when E is --CH₂ --CHR₄ --, and wherein Q is##SPC13##

wherein C_(t) H_(2t), T, and s are as defined above.

The various 3-oxa and 4-oxa phenyl-substituted dihydro-PGE₁,dihydro-PGF₁.sub.α, dihydro-PGF₁.sub.β, dihydro-PGA₁, and dihydro-PGB₁type compounds encompassed by Formulas XVII, XVIII, XXV, XXVI, XXXIII,XXXIV, XLI, and XLII are prepared by carbon-carbon double bond reductionof the corresponding PGE, PGF.sub.α, PGF.sub.β, PGA, and PGB typecompound containing a trans double bond in the hydroxy-containing sidechain. A cis or trans double bond or an acetylenic bond can also bepresent in the carboxy-terminated side chain of the unsaturatedreactant, and will be reduced at the same time to --CH₂ CH₂ --. Forexample, 13,14-dihydro-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ is producedby reduction of 3-oxa-17-phenyl-18,19,20-trinor-PGE₁,3-oxa-17-phenyl-18,19,20-trinor-PGE₂, or5,6-dehydro-3-oxa-17-phenyl-18,19,20-trinor-PGE₂. ##SPC14##

These reductions are carried out by reacting the unsaturated PGE,PGF.sub.α, PGF.sub.β, PGA or PGB type compound with diimide, followingthe general procedure described by van Tamelen et al., J. Am. Chem. Soc.83, 3725 (1961). See also Fieser et al., "Topics in Organic Chemistry,"Reinhold Publishing Corp., New York, pp. 432-434 (1963) and referencescited therein. The unsaturated acid or ester reactant is mixed with asalt of azodiformic acid, preferably an alkali metal salt such as thedisodium or dipotassium salt, in the presence of an inert diluent,preferably a lower alkanol such as methanol or ethanol, and preferablyin the absence of substantial amounts of water. At least one molecularequivalent of the azodiformic acid salt is used for each multiple bondequivalent of the unsaturated reactant. The resulting suspension is thenstirred, preferably with exclusion of oxygen, and the mixture is madeacid, advantageously with a carboxylic acid such as acetic acid. When areactant wherein R₁ is hydrogen is used, the carboxylic acid reactantalso serves to acidify an equivalent amount of the azodiformic acidsalt. A reaction temperature in the range of about 10° to about 40° C.is usually suitable. Within that temperature range, the reaction isusually complete within less than 24 hours. The desired dihydro productis then isolated by conventional methods, for example, evaporation ofthe diluent, followed by separation from inorganic materials by solventextraction.

In the case of the 3-oxa and 4-oxa phenyl-substituted unsaturated PGE,PGF.sub.α, and PGF.sub.β type reactants, the reductions to thecorresponding 3-oxa and 4-oxa phenyl-substituted dihydro-PGE₁,dihydro-PGF₁ .sub.α, and dihydro-PGF₁ .sub.β compounds are also carriedout by catalytic hydrogenation. For that purpose, palladium catalysts,especially on a carbon carrier, are preferred. It is also preferred thatthe hydrogenation be carried out in the presence of an inert liquiddiluent, for example, methanol, ethanol, dioxane, ethyl acetate, and thelike. Hydrogenation pressures ranging from about atmospheric to about 50p.s.i., and hydrogenation temperatures ranging from about 10° to about100° C. are preferred. The resulting dihydro product is isolated fromthe hydrogenation reaction mixture by conventional methods, for example,removal of the catalyst by filtration or centrifugation, followed byevaporation of the solvent.

Diimide reductions and catalytic hydrogenations to produce the variousnovel 3-oxa and 4-oxa phenyl-substituted dihydro compounds of thisinvention from the corresponding 3-oxa and 4-oxa PGE₁, PGF₁.sub.α,PGF₁.sub.β, PGA₁, and PGB₁ type compounds are shown in Chart B, whereinR₁, R₂, R₃ R₄, Q, and ˜ are as defined above, and W is --C_(n) H_(2n)--O--CR₅ R₆ -- or --C_(m) H_(2m) --O--CR₅ R₆ --CR₇ R₈ --, wherein n, m,R₅, R₆, R₇, and R₈ are defined above.

Diimide reductions and catalytic hydrogenations to produce the samenovel 3-oxa and 4-oxa phenyl-substituted dihydro compounds of thisinvention from the corresponding 3-oxa and 4-oxa phenyl-substitutedPGE₂, PGF₂ .sub.α, PGF₂ .sub.β, PGA₂, and PGB₂ type compounds and alsofrom the corresponding compounds with a trans-ethylenic or an acetyleniclinkage in place of the cis-ethylenic linkage in the carboxyl-terminatedside chain, are shown in Chart C, wherein R₁, R₂, R₃, R₄, Q, and ˜ areas defined above, U is cis --CH=CH--, trans --CH=CH--, or --C.tbd.C--,and Y is --C_(p) H_(2p) --O--CR₅ R₆ -- or --C_(q) H_(2q) --O--CR₅ R₆--CR₇ R₈ --, wherein p, q, R₅, R₆, R₇, and R₈ are as defined above.##SPC15## ##SPC16##

The 3-oxa and 4-oxa phenyl-substituted compounds of the PGE₂, PGF₂.sub.α, PGF₂ .sub.β, PGA₂, and PGB₂ type wherein the carbon-carbondouble bond in the carboxy-terminated side chain is in cis configurationare prepared by reduction of the corresponding acetylenic 3-oxa and4-oxa phenyl-substituted compounds, i.e., those with a carbon-carbontriple bond in place of said carbon-carbon double bond. For thatpurpose, there are used any of the known reducing agents which reduce anacetylenic linkage to a cis-ethylenic linkage. Especially preferred forthat purpose are diimide, or hydrogen and a catalyst, for example,palladium (5%) on barium sulfate, especially in the presence ofpyridine. See Fieser et al., "Reagents for Organic Synthesis," pp.566-567, John Wiley & Sons, Inc., New York, N.Y. (1967). Thesereductions are shown in Chart D, wherein R₁, R₂, R₄ Q, Y, and ˜ are asdefined above. These 3-oxa and 4-oxa phenyl-substituted cis compounds ofthe PGE₂, PGF₂ .sub.α, PGF₂ .sub.β, PGA₂, and PGB₂ type are alsoprepared as described hereinafter.

The 3-oxa and 4-oxa phenyl-substituted PGE type compounds of Formulas XIto XVI except wherein R₁ is hydrogen, and the 3-oxa and 4-oxaphenyl-substituted PGA type compounds of Formulas XXVII to XXXII exceptwherein R₁ is hydrogen are prepared by the series of reactions shown inChart E, wherein Q, R₂, R₃, R₄, and V are as defined above; Q' is##SPC17##

wherein T' is the same as T above except that R₉ is not hydrogen, R₁₀ isthe same as the above definition of R₁ except that R₁₀ does not includehydrogen; R₁₁ and R₁₂ are alkyl of one to 4 carbon atoms, inclusive; R₁₃is alkyl of one to 5 carbon atoms, inclusive; and ˜ indicates attachmentof --CHR₂ --V--COOR₁₀ to the cyclopentane ring in alpha or betaconfiguration, and exo or endo configuration with respect to the moietyattached to the cyclopropane ring. ##SPC18## ##SPC19##

The 3-oxa and 4-oxa phenyl-substituted PGE₁ type compounds of FormulasXI and XII, the 3-oxa and 4-oxa phenyl-substituted 5,6-dehydro-PGE₂ typecompounds of Formulas XV and XVI, the 3-oxa and 4-oxa phenyl-substitutedPGA₁ type compounds of Formulas XXVII and XXVIII and the 3-oxa and 4-oxaphenyl-substituted 5,6-dehydro-PGA₂ type compounds of Formulas XXXI andXXXII are also prepared by the series of reactions shown in Chart F,wherein Q, R₂, R₃, R₄, R₁₀, and R₁₃, are as defined above; Q' is##SPC20##

wherein T' is the same as T above except that R₉ is not hydrogen; Z is--C_(n) H_(2n) --O--CR₅ R₆ --, --C_(m) H_(2m) --O--CR₅ R₆ --CR₇ R₈ --,--C.tbd.C--C_(p) H_(2p) --O--CR₅ R₆ --, or --C.tbd.C--C_(q) H_(2q)--O--CR₅ R₆ --CR₇ R₈ --, and ˜ indicates attachment of --CHR₂--Z--COOR₁₀ to the cyclopentane ring in alpha or beta configuration, andexo or endo configuration with respect to the moiety attached to thecyclopropane ring.

It should be observed regarding the series of reactions shown in ChartsE and F, that the reactions starting with glycol XLV in Chart E aresimilar to the reactions starting with glycol LII in Chart F. The onlydifferences here are the definitions of the divalent moieties V (ChartE) and Z (Chart F). V includes saturated, cis and trans ethylenic, andacetylenic divalent moieties. Z is limited to the saturated andacetylenic divalent moieties encompassed by V. In other words, final3-oxa and 4-oxa phenyl-substituted PGE type compounds of Formula XLVII(Chart E) encompass compounds of Formulas XI to XVI. Final 3-oxa and4-oxa phenyl-substituted PGA type compounds of Formula XLVIII (Chart E)encompass compounds of Formulas XXVII to XXXII. On the other hand, final3-oxa and 4-oxa phenyl-substituted PGE type compounds of Formula LIV(Chart F) encompass only compounds of Formulas XI, XII, XV, and XVI, andfinal 3-oxa and 4-oxa phenyl-substituted PGA type compounds of FormulaLV (Chart F) encompass only compounds of Formulas XXVII, XXVIII, XXXI,and XXXII. ##SPC21##

As will subsequently appear, an acetylenic intermediate of FormulasXLIV, XLV, or LII is transformed by stepwise reduction to thecorresponding cis or trans ethylenic intermediates of Formulas XLIV orXLV; and an acetylenic intermediate of Formulas XLIV, XLV, or LII, or acis or trans ethylenic intermediate of Formulas XLIV or XLV istransformed by reduction to the corresponding saturated intermediate ofFormulas XLIV, XLV, or LII.

The initial bicyclo-ketone reactant of Formula L in Chart F is also usedas an initial reactant to produce the initial bicyclo-ketone cyclicketal reactant of Formula XLIII in Chart E. The following reactions willproduce cyclic ketal XLIII, wherein THP is tetrahydropyranyl, and φ isphenyl: ##SPC22##

The initial bicyclo-ketone reactant of Formula L exists in four isomericforms, exo and endo with respect to the attachment of the --CR₄ =CR₃ Qmoiety, and cis and trans with respect to the double bond in that samemoiety. Each of those isomers separately or various mixtures thereof areused as reactants according to this invention to produce substantiallythe same final 3-oxa and 4-phenyl-substituted PGE or PGA type productmixture.

The process for preparing either the exo or endo configuration of theFormula-L bicyclo-ketone is known to the art. See Belgian Pat. No.702,477; reprinted in Farmdoc Complete Specifications, Book 714, No.30,905, page 313, Mar. 12, 1968. See West Germany OffenlegungsschriftNo. 1,937,912; reprinted in Farmdoc Complete Specifications, Book No.14, No. 6869 R, Week R₅, Mar. 18, 1970.

In said Belgian Pat. No. 702,477, a reaction sequence capable of formingexo ketone L is as follows: The hydroxy of 3-cyclopentenol is protected,for example, with a tetrahydropyranyl group. Then a diazoacetic acidester is added to the double bond to give an exo-endo mixture of abicyclo[3.1.0]hexane substituted at 3 with the protected hydroxy and at6 with a esterified carboxyl. The exo-endo mixture is treated with abase to isomerize the endo isomer in the mixture to more of the exoisomer. Next, the carboxylate ester gruop at 6 is transformed to analdehyde group or ketone group, ##EQU1## wherein R₄ is as defined above.Then, said aldehyde group or said keto group is transformed by theWittig reaction, in this case to a moiety of the formula --CR₄ =CR₃ Qwhich is in exo configuration relative to the bicyclo ring structure.Next, the protective group is removed to regenerate the 3-hydroxy whichis then oxidized, for example, by the Jones reagent, i.e., chromic acid(see J. Chem. Soc. 39 (1946)), to give said exo ketone L.

Separation of the cis-exo and trans-exo isomers of L is described insaid Belgian Pat. No. 702,477. However, as mentioned above, thatseparation is usually not necessary since the cis-trans mixture isuseful as a reactant in the next process step.

The process described in said Belgian Pat. No. 702,477 for producing theexo form of bicyclo-ketone L uses, as an intermediate, the exo form of abicyclo[3.1.0]hexane substituted at 3 with a protected hydroxy, e.g.,tetrahydropyranyloxy, and at 6 with an esterified carboxyl. When thecorresponding endo compound is substituted for that exo intermediate,the process in said Offenlegungsschrift No. 1,937,912 leads to the endoform of bicyclo-ketone L. That endo compound to be used has the formula:##SPC23##

Compound LIX is prepared by reactingendo-bicyclo[3.1.0]hex-2-ene-6-carboxylic acid methyl ester withdiborane in a mixture of tetrahydrofuran and diethyl ether, a reactiongenerally known in the art, to giveendo-bicyclo[3.1.0]hexan-3-ol-6-carboxylic acid methyl ester which isthen reacted with dihydropyran in the presence of a catalytic amount ofPOCl₃ to give the desired compound. This is then used as described insaid Offenlegungsschrift No. 1,937,912 to produce the endo form ofbicyclo-ketone L.

As for exo L, the above process produces a mixture of endo-cis andendo-trans compounds. These are separated as described for theseparation of exo-cis and exo-trans L, but this separation is usuallynot necessary since, as mentioned above, the cis-trans mixture is usefulas a reactant in the next process step.

In the processes of said Belgian patent and said Offenlegungsschrift,certain organic halides, e.g., chlorides and bromides, are necessary toprepare the Wittig reagents used to generate the generic moiety --CR₄=CR₃ Q of bicyclo-ketone L. These organic chlorides and bromides##EQU2## are known in the art or can be prepared by methods known in theart.

To illustrate the availability of these organic chlorides and bromides,consider the above-described 3-oxa and 4-oxa phenyl-substituted PGE typecompounds of Formulas XI to XVIII, wherein C_(t) H_(2t) represents avalence bond or alkylene of one to 10 carbon atoms, inclusive,substituted with zero, one, or 2 fluoro, with one to 7 carbon atoms,inclusive, between --CR₃ OH-- and the phenyl ring; wherein T is alkyl ofone to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or--OR₉, wherein R₉ is hydrogen, alkyl of one to 4 carbon atoms,inclusive, or tetrahydropyranyl, and s is zero, one, 2, or 3, with theproviso that not more than two T are other than alkyl; and wherein R₃ ishydrogen or alkyl of one to 4 carbon atoms, inclusive. The halidesnecessary to prepare those compounds, if not readily available, areadvantageously prepared by reacting the corresponding primary alcohol,##SPC24##

or secondary alcohol ##SPC25##

with PCl₃, PBr₃, HBr, or any of the other halogenating agents known inthe art to be useful for this purpose.

In the case of R₃ being H, some of the readily available halides areshown in Table I wherein s, T, and t of the formula for the intermediatehalides are as defined above, and Hal is chloro, bromo, or iodo. Thus,compound No. 1 of Table I is represented by the formula wherein S and tare zero, and Hal is chloro, i.e. ##SPC26##

namely α-chlorotoluene or benzyl chloride; compound No. 8 of Table I isrepresented by the formula wherein s is zero, t is 2, and Hal is bromo,i.e. ##SPC27##

namely 1-bromo-3-phenylpropane or 3-bromopropylbenzene; and compound No.63 of Table I represented by the formula wherein s is 3, T is methyl inthe 2-, 4- and 5- positions with respect to the C_(t) H_(2t)substitution, t is 2, and Hal is bromo, i.e., ##SPC28##

namely 1-(3-bromophenyl)-2,4,5-trimethylbenzene.

                  TABLE I                                                         ______________________________________                                        Intermediate Halides                                                          represented by the formula                                                    No.     s         T           t       Hal                                     ______________________________________                                        1       0         --          0       Cl                                      2       0         --          0       Br                                      3       0         --          0       I                                       4       0         --          1       Cl                                      5       0         --          1       Br                                      6       0         --          1       I                                       7       0         --          2       Cl                                      8       0         --          2       Br                                      9       0         --          2       I                                       10      0         --          3       Cl                                      11      0         --           3*     Cl                                      12      0         --          3       Br                                      13      0         --          4       Cl                                      14      1         2-CH.sub.3  0       Cl                                      15      1         2-C.sub.2 H.sub.5                                                                         0       Cl                                      16      1         4-C.sub.2 H.sub.5                                                                         0       Cl                                      17      1         2-CF.sub.3  0       Cl                                      18      1         4-OCH.sub.3 0       Cl                                      19      1         3-CH.sub.3  0       Br                                      20      1         4-CH.sub.3  0       Br                                      21      1         C-C.sub.5 H.sub.11                                                                        0       Br                                      22      1         4-Cl        0       Br                                      23      1         2-CF.sub.3  0       Br                                      24      1         3-CF.sub.3  0       Br                                      25      1         4-CH.sub.3  0       I                                       26      1         4-F         1       Cl                                      27      1         3-Cl        1       Br                                      28      1         4-Cl        1       Br                                      29      1         4-F         1       Br                                      30      1         2-Cl        2       Br                                      31      1         3-Cl        2       Br                                      32      1         4-Cl        2       Br                                      33      1         4-F          3*     Br                                      34      1         2-Cl        4       Br                                      35      2         2-CH.sub.3  0       Cl                                                        4-CH.sub.3                                                  36      2         2-CH.sub.3  0       Cl                                                        5-CH.sub.3                                                  37      2         2-CH.sub.3  0       Cl                                                        6-CH.sub.3                                                  38      2         3-CH.sub.2  0       Cl                                                        4-CH.sub.3                                                  39      2         2-CH.sub.3  0       Cl                                                        4-Cl                                                        40      2         2-CH.sub.3  0       Br                                                        5-CH.sub.3                                                  41      2         2-CH.sub.3  0       Br                                                        6-CH.sub.3                                                  42      2         3-CH.sub.3  0       Br                                                        5-t-butyl                                                   43      2         3-CH.sub.3  0       Br                                                        4-Cl                                                        44      2         2-CH.sub.3  0       Br                                                        3-Br                                                        45      2         3-OCH.sub.3 0       Cl                                                        4-OCH.sub.3                                                 46      2         3-OCH.sub.3 0       Cl                                                        5-OCH.sub.3                                                 47      2         3-OCH.sub.3 0       Br                                                        5-OCH.sub.3                                                 48      2         2-CH.sub.3  1       Cl                                                        4-CH.sub.3                                                  49      2         2-CH.sub.3  1       Br                                                        4-CH.sub.3                                                  50      2         3-CH.sub.3  1       Br                                                        4-CH.sub.3                                                  51      2         3-OCH.sub.3 1       Br                                                        4-OCH.sub.3                                                 52      2         3-OCH.sub.3 1       Br                                                        5-OCH.sub.3                                                 53      2         3-OCH.sub.3 1       I                                                         4-OCH.sub.3                                                 54      2         3-OCH.sub.3 2       Br                                                        4-OCH.sub.3                                                 55      2         3-OCH.sub.3 2       Br                                                        5-OCH.sub.3                                                 56      2         3-OCH.sub.3 4       Br                                                        5-OCH.sub.3                                                 57      3         2-CH.sub.3  0       Cl                                                        4-CH.sub.3                                                                    5-CH.sub.3                                                  58      3         2-CH.sub.3  0       Cl                                                        4-CH.sub.3                                                                    6-CH.sub.3                                                  59      3         4-CH.sub.3  0       Cl                                                        2-OCH.sub.3                                                                   5-OCH.sub.3                                                 60      3         2-CH.sub.3  0       Br                                                        3-CH.sub.3                                                                    6-CH.sub.3                                                  61      3         2-CH.sub.3  0       Br                                                        4-CH.sub.3                                                                    6-CH.sub.3                                                  62      3         2-CH.sub.3  0       Br                                                        3-OCH.sub.3                                                                   6-OCH.sub.3                                                 63      3         2-CH.sub.3  2       Br                                                        4-CH.sub.3                                                                    5-CH.sub.3                                                  ______________________________________                                        *--branched--CH--                                                             |                                                                    Et                                                                        

In the case of R₃ being alkyl, some of the readily available halides areshown in Table II. Thus, compound No. 1 of Table II is represented bythe formula wherein s and t are zero, R₃ is methyl, and Hal is chloro,i.e. ##SPC29##

namely (1-chloroethyl)benzene; and compound No. 13 of Table II isrepresented by the formula wherein s is 2, t is one, R₃ and T aremethyl, and Hal is bromo, i.e. ##SPC30##

namely 4-(2-bromopropyl)-o-xylene or1-(2-bromopropyl)-3-methyl-4-methylbenzene.

                  TABLE II                                                        ______________________________________                                        Intermediate Halides                                                          represented by the Formula                                                    No.    s        T          R.sub.3                                                                              t     Hal                                   ______________________________________                                        1      0        --         CH.sub.3                                                                             0     Cl                                    2      0        --         C.sub.2 H.sub.5                                                                      0     Cl                                    3      0        --         C.sub.2 H.sub.5                                                                      0     Br                                    4      0        --         CH.sub.3                                                                             0     I                                     5      0        --         CH.sub.3                                                                             1     Cl                                    6      0        --         n-C.sub.3 H.sub.7                                                                    1     Cl                                    7      0        --         CH.sub.3                                                                             1     Br                                    8      0        --         C.sub.2 H.sub.5                                                                      2     Cl                                    9      1        4-C.sub.2 H.sub.5                                                                        CH.sub.3                                                                             0     Cl                                    10     1        4-F        CH.sub.3                                                                             0     Cl                                    11     1        4-Cl       C.sub.2 H.sub.5                                                                      O     Br                                    12     1        4-F        C.sub.2 H.sub.5                                                                      0     Br                                    13     2        3-CH.sub.3 CH.sub.3                                                                             1     Br                                                    4-CH.sub.3                                                    14     2        3-OCH.sub.3                                                                              CH.sub.3                                                                             1     Br                                                    4-OCH.sub.3                                                   15     2        2-OCH.sub.3                                                                              CH.sub.3                                                                             1     Br                                                    6-OCH.sub.3                                                   ______________________________________                                    

Other intermediate halides of the general formula ##SPC31##

may be obtained from the primary or secondary alcohols as discussedabove. These alcohols are in general prepared from correspondingcarboxylic acids. Thus, the substituted benzoic acids are selectivelyreduced to the corresponding benzyl using any of several hydridereagents, e.g., sodium borohydride/aluminum chloride in diglyme,diborane in tetrahydrofuran, aluminum hydride in tetrahydrofuran, andthe like. The secondary alcohols, wherein R₃ is alkyl, are prepared bytransforming the COOH of the corresponding carboxylic acid, ##SPC32##

to a ketone by known procedures, e.g. by way of the acyl chloride and adialkylcadmium. Reduction of the ketone with sodium borohydride thenyields the secondary alcohol, ##SPC33##

Hydroxyl groups of the aromatic ring are suitably protected during thesereactions by first forming the corresponding tetrahydropyranyl etherswith dihydropyran; the hydroxyl groups are restored by mild acidhydrolysis as is well known in the art.

In the case of C_(t) H_(2t) substituted with one or 2 fluoro atoms,there are a number of routes to the intermediate halides. Thecorresponding alcohols, for example β-fluorophenethyl alcohol,β-fluoro-α-methyl-phenethyl alcohol, β-fluoro, α,β-dimethyl-phenethylalcohol, and the like, are reacted with PCl₃ PBr or HBr to form thehalide. Alternatively, the carboxylic acid having one less carbon atomsin the chain than the desired intermediate halide, i.e. ##SPC34##

wherein g is t-1, is converted by a series of known methods to the2,2-difluorohalide. Thus, the free carboxyl group is transformed firstto the acid chloride with thionyl chloride and thence by way of thenitrile to the α-keto-acid. The carboxyl group is reduced to the alcoholwith diborane and then converted to the α-keto halide. Finally, byreaction of the keto group with sulfur tetrafluoride, there is obtained##SPC35##

For reactions of SF₄ see U.S. Pat. No. 3,211,723 and J. Org. Chem. 27,3164 (1962).

As mentioned above, Formula XI-to-XLII compounds with an alpha-fluorosubstituent on the carbon adjacent to the hydroxy-substituted carbon(i.e. adjacent to C-15 in PGE₁) represent preferred embodiments amongthe novel phenyl-substituted compounds of this invention. The Formula-Lbicyclo-ketones necessary to produce those mono-fluoro compounds areadvantageously prepared by reacting either of the above-mentionedbicyclo-aldehydes, exo or endo, with a Wittig reagent prepared from##SPC36##

and triphenylphosphine. The aldehyde group is thereby transformed to##SPC37##

The resulting unsaturated ketone is reduced to the corresponding##EQU3## compound. Then --OH in that group is replaced with fluoro byknown methods, for example, directly by reaction with2-chloro-1,1,2-trifluorotriethylamine or indirectly for example, bytransforming the hydroxy to tosyloxy or mesyloxy, and reacting theresulting compound with anhydrous potassium fluoride in diethyleneglycol.

The transformation of bicyclo-ketone-olefin L to glycol LVIII is carriedout by reacting olefin L with a hydroxylation reagent. Hydroxylationreagents and procedures for this purpose are known in the art. See, forexample, Gunstone, Advances in Organic Chemistry, Vol. 1, pp. 103-147,Interscience Publishers, New York, N.Y. (1960). Various isomeric glycolsare obtained depending on such factors as whether olefin L is cis ortrans and endo or exo, and whether a cis or a trans hydroxylationreagent is used. Thus endo-cis olefin L gives a mixture of two isomericerythro glycols of Formula LVIII with a cis hydroxylation agent, e.g.,osmium tetroxide. Similarly, the endo-trans olefin L gives a similarmixture of the same two erythro glycols with a trans hydroxylationagent, e.g., hydrogen peroxide. The endo-cis olefins and the endo-transolefins L give similar mixtures of two threo glycol isomers with cis andtrans hydroxylation reagents, respectively. These various glycolmixtures are separated into individual isomers by silica gelchromatography. However, this separation is usually not necessary, sinceeach isomeric erythro glycol and each isomeric threo glycol is useful asan intermediate according to this invention and the processes outlinedin Chart E to produce final products of Formulas XLVII and XLVIII, andthen, according to Charts A, B, C, and D to produce the other finalproducts of this invention. Thus, the various isomeric glycol mixturesencompassed by Formula LVIII produced from the various isomeric olefinsencompassed by Formula L are all useful for these same purposes.

The transformation of glycol LVIII to the cyclic ketal of Formula XLIII(Chart E) is carried out by reacting said glycol with a dialkyl ketoneof the formula ##EQU4## wherein R₁₁ and R₁₂ are alkyl of one to 4 carbonatoms, inclusive, in the presence of an acid catalyst, for examplepotassium bisulfate or 70% aqueous perchloric acid. A large excess ofthe ketone and the absence of water is desirable for this reaction.Examples of suitable dialkyl ketones are acetone, methyl ethyl ketone,diethyl ketone, methyl propyl ketone, and the like. Acetone is preferredas a reactant in this process.

Referring again to Chart E, cyclic ketal XLIII is transformed to cyclicketal XLIV by alkylating with an alkylation agent of the formula##EQU5## wherein R₂, R₁₀, and V are as defined above, and Hal ischlorine, bromine, or iodine. Similarly, referring to Chart F, olefin Lis transformed to olefin LI by alkylating with an alkylation agent ofthe formula ##EQU6## wherein R₂, R₁₀, Z, and Hal are as defined above.

Any of the alkylation procedures known in the art to be useful foralkylating cyclic ketones with alkyl halides and haloalkanoic esters areused for the transformations of XLIII to XLIV, and of L to LI. See, forexample, the above-mentioned Belgian Pat. No. 702,477 for proceduresuseful here and used there to carry out similar alkylations.

For these alkylations, it is preferred that Hal be bromo or iodo. Any ofthe usual alkylation bases, e.g., alkali metal alkoxides, alkali metalamides, and alkali metal hydrides, are useful for this alkylation.Alkali metal alkoxides are preferred, especially tert-alkoxides. Sodiumand potassium are preferred alkali metals. Especially preferred ispotassium tert-butoxide. Preferred diluents for this alkylation aretertrahydrofuran and 1,2-dimethoxyethane. Otherwise, procedures forproducing and isolating the desired Formula XLIV and -LI compounds arewithin the skill of the art.

These alkylation procedures produce mixtures of alpha and betaalkylation products, i.e., a mixture of Formula-XLIV products whereinpart has the --CHR₂ --V--COOR₁₀ moiety attached in alpha configuration,and wherein part has that moiety attached in beta configuration, or amixture of Formula-LI products with the --CHR₂ --Z--COOR₁₀ moiety inboth alpha and beta configurations. When about one equivalent of baseper equivalent of Formula-XLIII or L ketone is used, the alphaconfiguration usually predominates. Use of an excess of base and longerreaction times usually result in production of larger amounts of betaproducts. These alpha-beta isomer mixtures are separated at this stageor at any subsequent stage in the multi-step processes shown in Charts Eand F. Silica gel chromatography is preferred for this separation.

The necessary alkylating agents for the above-described alkylations,i.e., compounds of the formulas ##EQU7## and ##EQU8## are prepared bymethods known in the art. There are eight groups of compoundsencompassed by these two genera or alkylating agents.

Alkylating agents of the formula ##EQU9## include compounds of theformulas: ##EQU10##

Alkylating agents of the formula ##EQU11## include the above-listedcompounds of Formulas LX, LXI, LXII, and LXIII, and also compounds ofthe following formulas: ##EQU12## These alkylating agents of Formulas LXto LXVII are accessible to those of ordinary skill in the art. Forexample, the 3-oxa alkylating agents of Formulas LX, LXII, LXIV, and LXVare advantageously prepared by reacting an alpha-hydroxy ester or acidof the formula HO--CR₅ R₆ --COOR₁, wherein R₁, R₅, and R₆ are as definedabove, with a compound of the formula, ##EQU13## respectively, whereinR₂, n, and p are as defined above, J is chloro, bromo, iodo, or a grouptransformable to one of those, for example, tetrahydropyranyloxy ormesyloxy, and K is chloro, bromo, iodo, mesyloxy, tosyloxy, or the like,in the presence of a strong base, for example, sodium hydride when R₁ isa carbon-containing group, and lithium diisopropyl amide when R₁ ishydrogen. Alternatively, an alpha-bromo ester or acid of the formulaBr--CR₅ R₆ --COOR₁, wherein R₁, R₅, and R₆ are as defined above, isreacted in the presence of a similar strong base with a compound of theformula ##EQU14## or J--CH--CH=CH--C_(p) H_(2p) --OH. When both R₅ andR₆ in the ester are alkyl, it is preferred to use the hydroxy acid orester route. When there are two alkyl groups in C_(n) H_(2n) or C_(p)H_(2p) on the carbon to which --OH or --K is attached, it is preferredto use the bromo acid or ester route. When a Formula LX, LXII, LXIV, orLXV alkylating agent is desired wherein both R₅ and R₆ are alkyl andC_(n) H_(2n) or C_(p) H_(2p) has two alkyl groups attached to the carbonto which --O-- is attached, it is preferred that K be mesyloxy ortosyloxy, or that the Br of the bromo acid or ester be replaced withmesyloxy or tosyloxy, and that relatively mild bases and reactionconditions be used, for example, potassium tert-butoxide in dimethylsulfoxide. Alternatively, this group of tetraalkyl compounds isadvantageously prepared by using the hydroxy acid or ester route whereinJ is chloro or by using the bromo acid or ester route wherein the bromois replaced with chloro, using freshly precipated wet magnesiumhydroxide in ethanol suspension as the base. Alternatively this group oftetraalkyl compounds is advantageously prepared by the hydroxy acid orester route wherein J is iodo, and silver oxide is used as the base. Anyof these alternative routes is, of course, useful to make the othercompounds within the scope of Formulas LX, LXII, LXIV, and LXV.

An alternative procedure generally applicable to the production of thealkylating agents of Formulas LX, LXII, LXIV, and LXV comprises reactinga compound of the formula ##EQU15## with an ethylene oxide of theformula ##EQU16## wherein R₅ and R₆ are as defined above, in thepresence of an acid catalyst, e.g., hydrochloric acid, sulfuric acid, orboron trifluoride. The alcohol which is usually the major product,##EQU17## or cis or trans ##EQU18## is isolated, oxidized to thecorresponding carboxylic acid with Jones reagent, and the acidesterified (R₁₀).

The 4-oxa alkylating agents of Formulas LXI, LXIII, LXVI, and LXVII areadvantageously prepared as described above for the 3-oxa compounds,combining compounds of the formula ##EQU19## with β-hydroxy acids oresters and β-halo acids or esters of the formulas HO--CR₅ R₆ --CR₇ R₈--COOR₁ and Br--CR₅ R₆ --CR₇ R₈ --COOR₁, or trimethylene oxides of theformula R₅ R₆ C--CR₇ R₈ --CH₂ --O.

All of the procedures, preferences, and alternatives described above forthe preparation of the 3-oxa alkylating agents are applicable to thepreparation of these 4-oxa alkylating agents.

The alkylating agents of Formulas LX to LXVII are esters. When an alphaor beta hydroxy acid or bromo acid is used as a reactant as describedabove, the resulting product is a carboxylic acid. This acid isesterified to the corresponding Formula LX-to-LXVII alkylating agent byknown procedures. As will be described hereinafter, the ester moiety R₁₀is chosen according to the desired type of final 3-oxa or 4-oxaprostaglandin-like product.

The alpha-hydroxy, alpha-halo, beta-hydroxy, and beta-halo acids andesters and the ethylene and trimethylene oxides used as described aboveto produce the Formula LX-to-LXVII alkylating agents are all known inthe art or are readily accessible through known methods to those ofordinary skill in the art.

The other reactants of the formulas ##EQU20## and the correspondingreactants with halogen, mesyloxy, or tosyloxy in place of --OH also areknown in the art or are readily accessible through known methods tothose of ordinary skill in the art.

For example, consider the compounds ##EQU21## wherein R₂ is hydrogen oralkyl of one to 4 carbon atoms, inclusive, as defined above, THPrepresents 2-tetrahydropyranyl, and each free valence -- is attached tohydrogen or to alkyl, with a total of zero to 9 attached carbon atoms.Said compounds are within the scope of ##EQU22## as above defined, andare advantageously prepared by hydroxylating by known methods, olefinsof the formula ##EQU23## to give the glycols ##EQU24## which aretransformed by known methods to the above tetrahydropyranyl ethers.These ethers are also transformed by known methods to ##EQU25##compounds within the scope of ##EQU26## as above defined.

Consider the compounds ##EQU27## wherein R₂ and THP are as abovedefined, and the free valences are attached to hydrogen or to alkyl,with a total of zero to 8 attached alkyl carbon atoms. Said compoundsare within the scope of ##EQU28## as above defined, and areadvantageously prepared by known methods from beta-hydroxyesters of theformula ##EQU29## wherein R₂ is as defined above, R₂₀ is methyl or ethyland the free valences are attached to hydrogen or to alkyl. Said estersare available through methods known in the art, e.g., the Reformatskyreaction. Said compounds are also transformed by known methods to##EQU30## compounds within the scope of ##EQU31## as above defined.

Consider the compounds ##EQU32## wherein R₂ and THP are as defined aboveand the free valences are attached to hydrogen or to alkyl, with a totalof zero to 7 attached alkyl carbon atoms. Said compounds are within thescope of ##EQU33## as above defined, and are advantageously prepared byknown methods from the known succinic acid half esters of the formula##EQU34## wherein R₂₀ is methyl or ethyl, the carboxyl end beingtransformed to ##EQU35## and then the --COOR₂₀ end being transformed to##EQU36## both by known methods. Said compounds are also transformed byknown methods to ##EQU37## compounds within the scope of ##EQU38## asabove defined.

Consider the compounds ##EQU39## wherein R₂ and THP are as defined aboveand the free valences are attached to hydrogen or to alkyl, with a totalof zero to 6 attached alkyl carbon atoms. Said compounds are within thescope of ##EQU40## as above defined, and are advantageously prepared byknown methods from ##EQU41## wherein THP, R₂, and the free valenceattachments are as above defined, and R₂₀ is methyl or ethyl. Theseester reactants are prepared by known methods from ##EQU42## reactantswhose preparation is described in the preceeding paragraph. Saidcompounds are also transformed by known methods to ##EQU43## compoundswithin the scope of ##EQU44## as above defined. In a similar manner,compounds of the formulas ##EQU45## and ##EQU46## wherein the freevalences are attached to hydrogen or to alkyl, with a total of zero to 5attached alkyl carbon atoms, are prepared from ##EQU47## compounds.

Consider the compounds ##EQU48## wherein R₂ and THP are as abovedefined, and the free valences are attached to hydrogen or to alkyl,with a total of zero to seven attached alkyl carbon atoms. Saidcompounds are within the scope of ##EQU49## as above defined, and areprepared by known methods from reactants of the formula ##EQU50## whichare known in the art or are prepared by known methods. See, for example,U.S. Pat. No. 3,108,140. Said compounds are also transformed by knownmethods to ##EQU51## compounds within the scope of ##EQU52## as abovedefined.

Consider the compounds ##EQU53## wherein R₂ and THP are as abovedefined, and the free valences are attached to hydrogen or to alkyl,with a total of zero to six attached alkyl carbon atoms. Said compoundsare within the scope of ##EQU54## as above defined, and are prepared byknown methods from the known or easily accessible beta-hydroxy esters ofthe formula ##EQU55## wherein R₂₀ is methyl or ethyl. The hydroxy end ofthose is changed to --O--THP and the R₂₀ OOC end is changed to ##EQU56##both by known methods. Then ##EQU57## is changed by known methods firstto HC.tbd.C-- and then to ##EQU58## Finally ##EQU59## is transformed byknown methods to ##EQU60## The latter is also transformed by knownmethods to ##EQU61## compounds within the scope of ##EQU62## as abovedefined.

Another route to compounds ##EQU63## as above defined comprisesReformatsky-type reactions of propargyl bromides of the formula##EQU64## with ketones or aldehydes ##EQU65## to give ##EQU66## See, forexample J. Chem. Soc. (London) 2696 (1949). Then --OH is changed to--O--THP and HC.tbd.C-- is changed to ##EQU67## both by known methods.Finally, ##EQU68## is changed to ##EQU69## by known methods.

Consider the compounds ##EQU70## wherein R₂ and THP are asabove-defined, and the free valences are attached to hydrogen or toalkyl, with a total of zero to 5 attached alkyl carbon atoms. Saidcompounds are within the scope of ##EQU71## as above defined, and areprepared by known methods from the known succinic acid half esters ofthe formula ##EQU72## wherein R₂₀ is methyl or ethyl. The carboxyl endis changed to Br-- and the --COOR₂₀ end is changed to ##EQU73## both byknown methods. Then, Br-- is changed first to HOOC-- and then to##EQU74## both by known methods. Then ##EQU75## is changed first toHC.tbd.C-- and then to ##EQU76## both by known methods. Finally,##EQU77## is transformed by known methods to ##EQU78## The latter isalso transformed by known methods to ##EQU79## compounds within thescope of ##EQU80## as above defined.

Another route to compounds of the formulas ##EQU81## both types withinthe scope of ##EQU82## as above defined comprises reaction of ##EQU83##by known procedures. These latter reactants are known or easilyaccessible by known methods.

The reactants of formulas ##EQU84## are prepared as described above forthe preparation of the corresponding C_(n) H_(2n) compounds, dueconsideration being given to the definition differences between C_(n)H_(2n) and C_(m) H_(2m). Similarly, reactants of formulas ##EQU85## areprepared as described above for the preparation of the correspondingC_(p) H_(2p) compounds, due consideration being given to the definitiondifferences between C_(p) H_(2p) and C_(q) H_(2q).

The cis and trans ethylenic reactants of formulas ##EQU86## are preparedby cis or trans reduction of the corresponding acetylenic reactantprepared as above described, or by cis or trans reduction of any earlieracetylenic intermediate in which both ends of the acetylenic bond aresubstituted, i.e., not hydrogen as in the moiety HC.tbd.C--.Alternatively, this cis or trans reduction is carried out on anysubsequent acetylenic reaction product leading up to and including thefinal acetylenic alkylating agent of Formula LXII or LXIII.

For these cis reductions of the acetylenic bonds, it is advantageous touse hydrogen plus a catalyst which catalyzes hydrogenation of--C.tbd.C-- only to cis --CH=CH--. Such catalysts and procedures arewell known to the art. See, for example, Fieser et al., "Reagents forOrganic Syntheses," pp. 566-567; John Wiley & Sons, Inc., New York, N.Y.(1967). Palladium (5%) on barium sulfate, especially in the presence ofpyridine as a diluent, is a suitable catalyst for this purpose.Alternative reagents useful to transform these acetylenic compounds tocis-ethylenic compounds are bis(3-methyl-2-butyl)borane("disiamylborane") and diisobutylaluminum hydride.

For trans reductions of the acetylenic bond, it is advantageous to usesodium or lithium in liquid ammonia or a liquid alkylamine, e.g.,ethylamine. When the moiety HO--CH₂ --C.tbd.C-- is present in theacetylenic compound being reduced, the use of lithium aluminum hydridegives trans reduction of the triple bond. Procedures for these transreductions are known in the art. See, for example, Fieser βabove cited,pp. 577, 592-594, and 603, and J. Am. Chem. Soc. 85, 622 (1963).

Referring again to Chart E, after alkylation as discussed above, cyclicketal LXIV is transformed to glycol XLV by reacting the cyclic ketalwith an acid with pK less than 5. Suitable acids and procedures forhydrolyzing cyclic ketals to glycols are known in the art. Suitableacids are formic acid, hydrochloric acid, and boric acid. Especiallypreferred as diluents for this reaction are tetrahydrofuran andβ-methoxyethanol.

Referring again to Chart F, after alkylation as discussed above, olefinLI is hydroxylated to glycol LII. As discussed above, the divalentmoiety --Z-- includes the moieties --C_(n) H_(2n) --O--CR₅ R₆ --,--C_(m) H_(2m) --O--CR₅ R₆ --CR₇ R₈ --, --C.tbd.C--C_(p) H_(2p) --O--CR₅R₆ --, and --C.tbd.C--C_(q) H_(2q) --O--CR₅ R₆ --CR₇ R₈ --, wherein m,n, p, q, R₅, R₆, R₇, and R₈ are as defined above. When Z is --C_(n)H_(2n) --O--CR₅ R₆ -- or --C_(m) H_(2m) --O--CR₅ R₆ --CR₇ R₈ --, thishydroxylation of LI is carried out as described above for thehydroxylation of olefin L to glycol LVIII, i.e., with any of the knownreagents and procedures described in Gunstone, above cited. When Z is--C.tbd.C--C_(p) H_(2p) --O--CR₅ R₆ -- or --C.tbd.C--C_(q) H_(2q)--O--CR₅ R₆ --CR₇ R₈ --, some of the reagents and procedures describedby Gunstone tend to attack the acetylenic linkage as well as theethylenic linkage of the Formula-LI olefin. Therefore it is preferred touse a hydroxylation reagent and procedure which attacks the ethyleniclinkage preferentially. For this, it is preferred to carry outhydroxylation of these acetylenic Formula-LI olefins with organicperacids, e.g., performic acid, peracetic acid, perbenzoic acid, andm-chloroperbenzoic acid, as described by Gunstone, above cited, pp.124-130.

As discussed above regarding the hydroxylation of unalkylated olefin Lto unalkylated glycol LVIII various isomeric glycols are obtained byhydroxylation of the Formula-LI alkylated olefin. The particularFormula-LII glycol or glycol mixture obtained depends on such factors aswhether the olefin LI is cis or trans and endo or exo, and whether a cisor a trans hydroxylation takes place. However, all of the isomericFormula-LI erytho and threo glycols and the various glycol mixtures eachare useful as an intermediate according to this invention and theprocesses of Chart F to produce final products of Formulas LIV and LV,and then according to Charts A, B, C, and D, to produce the other finalproducts of this invention. Therefore, it is usually not necessary toseparate individual Formula-LI glycol isomers before proceeding furtherin the synthesis, although that separation is accomplished by silica gelchromatography.

It is preferred that glycols XLV and LII of Charts E and F,respectively, be free of phenolic hydroxyl substituents before thealkanesulfonation step. If any of the intermediate Formula-XLV orFormula-LII compounds have phenolic hydroxyls, these hydroxyls arereadily converted to tetrahydropyranyloxy (OTHP) by reaction withdihydropyran, e.g. in the presence of a catalytic amount of POCl₃. The--OTHP group is subsequently replaced by OH under neutral or mildlyacidic conditions.

Referring again to Charts E and F, bis(alkanesulfonic acid) esters XLVIand LIII are prepared by reacting glycols XLV and LII, respectively,with an alkanesulfonyl chloride or bromide, or with an alkanesulfonicacid anhydride, the alkyl in each containing one to 5 carbon atoms,inclusive. Alkanesulfonyl chlorides are preferred for this reaction. Thereaction is carried out in the presence of a base to neutralize thebyproduct acid. Especially suitable bases are tertiary amines, e.g.,dimethylaniline or pyridine. It is usually sufficient merely to mix thetwo reactants and the base, and maintain the mixture in the range 0° to25°C. for several hours. The Formula-XLVI and LIII bis(sulfonic acid)esters are then isolated by procedures known to the art.

Referring now to Chart E, bis(sulfonic acid) esters XLVI are transformedeither to 3-oxa or 4-oxa phenyl-substituted PGE type compounds XLVII, orto 3-oxa and 4-oxa phenyl-substituted PGA type compounds XLVIII.Referring to Chart F, bis(sulfonic acid) esters LIII are transformedeither to 3-oxa and 4-oxa phenyl-substituted PGE type compounds LIV, orto 3-oxa and 4-oxa phenyl-substituted PGA type compounds LV.

The transformations of XLVI and LIII to the PGE type compounds XLVII andLIV, respectively, are carried out by reacting bis-esters XLVI and LIIIwith water in the range about 0° to about 60° C. In making the 3-oxa and4-oxa phenyl-substituted PGE₁ compounds, 25° C. is a suitable reactiontemperature, the reaction then proceeding to completion in about 5 to 20hours. It is advantageous to have a homogenous reaction mixture. This isaccomplished by adding sufficient of a water-soluble organic diluentwhich does not enter into the reaction. Acetone is a suitable diluent.The desired product is isolated by evaporation of excess water anddiluent if one is used. The residue contains a mixture of Formula-XLVIIor Formula-LIV isomers which differ in the configuration of the sidechain hydroxy, that being either S or R. These are separated frombyproducts and from each other by silica gel chromatography. A usualbyproduct is the mono-sulfonic acid ester of Formula XLIX (Chart E) orFormula LVI (Chart F). These mono-sulfonic acid esters are esterified tothe Formula-XLVI or -LIII bis(sulfonic acid) esters, respectively, inthe same manner described above for the transformation of glycol XLV orLII to bis-ester XLVI or LIII and thus are recycled back to additionalFormula XLVII or LIV final product.

The transformations of XLVI and LIII to the PGA type compounds XLVIIIand LV, respectively, are carried out by heating bis-esters XLVI andLIII in the range 40° to 100° C. with a combination of water, a basecharacterized by its water solution having a pH 8 to 12, and sufficientinert water-soluble organic diluent to form a basic and substantiallyhomogenous reaction mixture. A reaction time of one to 10 hours isusually used. Preferred bases are the watersoluble salts of carbonicacid, especially alkali metal bicarbonates, e.g., sodium bicarbonate. Asuitable diluent is acetone. The products are isolated and separated asdescribed above for the transformation of bis-esters XLVI and LIII toPGE type products XLVII and LIV. The same mono-sulfonic acid esters XLIXand LVI observed as byproducts in those tranformations are also observedduring preparation of PGA type products XLVIII and LV.

For the transformations of bis(sulfonic acid) esters XLVI and LIII tofinal products XLVII, XLVIII, LIV, and LV, it is preferred to use thebis-mesyl esters, i.e., compounds XLVI and LIII wherein R₁₃ is methyl.

Referring again to Charts E and F, the configuration of the ##EQU87##moiety in the Formula-XLVI bis-esters or the configuration of the##EQU88## moiety in the Formula-LIII bis-esters does not change duringthese transformations of XLVI to XLVII, XLVIII, and XLIX, and of LIII toLIV, LV, and LVI. Therefore, when in Formula XLVI for example, V is--(CH₂)₂ --O--(CH₂)₂ --, Q is ##SPC38##

and R₂, R₃ and R₄ are hydrogen, S and R 4-oxa-18-phenyl-19,20-dinor-PGE₁esters (XLVII) are obtained when ##EQU89## is attached initially (XLVI)in alpha configuration, and S and R8-iso-4-oxa-18-phenyl-19,20-dinor-PGE₁ esters (XLVII) are obtained whenthat moiety is attached in beta configuration. Similarly, when inFormula XLVI, V is cis--CH=CH--CH₂ --O--CH₂ -- or --C.tbd.CCH₂ --O--CH₂--, Q is ##SPC39##

and R₂, R₃, and R₄ are hydrogen, S and R3-oxa-17-phenyl-18,19,20-trinor-PGE₂ esters and S and R5,6-dehydro-3-oxa-17-phenyl-18,19,20-trinor-PGE₂ esters are obtainedwhen ##EQU90## is attached initially in alpha configuration, and thecorresponding 8-iso compounds are obtained when that moiety is attachedin beta configuration. The same retention of ##EQU91## configurationoccurs when Formula-XLVIII and XLIX compounds are produced, and asimilar retention of ##EQU92## configuration occurs when Formula-LIV,LV, and LVI compounds are produced from Formula-LIII bis-esters.

The Formula-XLVII and LIV 3-oxa and 4-oxa phenyl-substituted PGE typecompounds and the Formula-XLVIII and LV 3-oxa and 4-oxaphenyl-substituted PGA type compounds shown in Charts E and F are allR₁₀ carboxylic acid esters, wherein R₁₀ is defined above. Moreover, whenthose PGE-type and PGA-type R₁₀ esters are used to prepare the other3-oxa and 4-oxa phenyl-substituted prostaglandin-like compoundsaccording to Charts A, B, C, and D, corresponding R₁₀ esters are likelyto be produced, especially in the case of the 3-oxa and 4-oxaphenyl-substituted PGF type compounds. For some of the uses describedabove, it is preferred that the novel Formula XI-to-XLII 3-oxa and 4-oxaphenyl-substituted prostaglandin-like compounds of this invention be infree acid form, or in salt form which requires the free acid as astarting material. The PGF-type esters of Formulas XIX to XXVI and thePGE-type compounds of Formulas XXXV to XLII are easily hydrolyzed orsaponified to the free acids by the usual known procedures, especiallywhen R₁ (R.sub. 10) is alkyl of one to 4 carbons, inclusive, preferablymethyl or ethyl.

On the other hand, the PGE type esters of Formulas XI to XVIII and thePGA type esters of Formulas XXVII to XXXIV are difficult to hydrolyze orsaponify without causing unwanted structural changes in the desiredacids. There are two other procedures to make the free acid forms ofthese Formula XI-to-XVIII and XXVII-to-XXXIV compounds.

One of those procedures is applicable mainly in preparing the free acidsfrom the corresponding alkyl esters wherein the alkyl group contains oneto 8 carbon atoms, inclusive. That procedure comprises subjecting thealkyl esters corresponding to Formulas XI to XVIII and XXVII to XXXIV tothe acylase enzyme system of a microorganism species of Subphylum 2 ofPhylum III, and thereafter isolating the acid. Especially preferred forthis purpose are species of the orders Mucorales, Hypocreales,Moniliales, and Actinomycetales. Also especially preferred for thispurpose are species of the families Mucoraceae, Cunninghamellaceae,Nectreaceae, Moniliaceae, Dematiaceae, Tuberculariaceae,Actinomycetaceae, and Streptomycetaceae. Also especially preferred forthis purpose are species of the genera Absidia, Circinella, Gongronella,Rhizopus, Cunninghamella, Calonectria, Asperigillus, Penicillium,Sporotrichum, Cladosporium, Fusarium, Nocardia, and Streptomyces.

Examples of microorganisms falling within the scope of those preferredorders, families, and genera are listed in U.S. Pat. No. 3,290,226.

This enzymatic ester hydrolysis is carried out by shaking the FormulaXI-to-XVIII or XXVII-to-XXXIV alkyl esters in aqueous suspension withthe enzyme contained in a culture of one of the above-mentionedmicroorganism species until the ester is hydrolyzed. A reactiontemperature in the range 20° to 30°C. is usually satisfactory. Areaction time of one to 20 hours in usually sufficient to obtain thedesired hydrolysis. Exclusion of air from the reaction mixture, forexample, with argon or nitrogen is usually desirable.

The enzyme is obtained by harvest of cells from the culture, followed bywashing and resuspension of the cells in water, and cell disintegration,for example, by stirring with glass beads or by sonic or ultrasonicvibrations. The entire aqueous disintegration mixture is used as asource of the enzyme. Alternatively and preferably, however, thecellular debris is removed by centrifugation or filtration, and theaqueous supernatant or filtrate is used.

In some cases, it is advantageous to grow the microorganism culture inthe presence of an alkyl ester of an aliphatic acid, said acidcontaining 10 to 20 carbon atoms, inclusive, and said alkyl containingone to 8 carbon atoms, inclusive, or to add such an ester to the cultureand maintain the culture without additional growth for one to 24 hoursbefore cell harvest. Thereby, the enzyme produced is sometimes moreeffective in transforming the Formula XI-to-XVIII or XXVII-to-XXXIVester to the free acid. An example of a useful alkyl ester for thispurpose is methyl oleate.

This enzymatic hydrolysis is also applicable to the Formula XIX-to-XXVIPGF type alkyl esters and the Formula XXXV-to-XLIII PGB type alkylesters.

Another procedure for making the free acids of Formula XI-to-XVIII PGEtype compounds and Formula XXVII-to-XXXIV PGA type compounds involvestreatment of certain haloethyl esters of those acids with zinc metal andan alkanoic acid of 2 to 6 carbon atoms, preferably acetic acid. Thosehaloethyl esters are the esters wherein R₁₀ is ethyl substituted in theβ-position with 3 chloro, 2 or 3 bromo, or one, 2, or 3 iodo. Of thosehaloethyl moieties, β,β,β-trichloroethyl is preferred. Zinc dust ispreferred as the physical form of the zinc. Mixing the haloethyl esterwith the zinc dust at about 25° C. for several hours usually causessubstantially complete replacement of the haloethyl moiety of theFormula XI-to-XVIII or XXVII-to-XXXIV ester with hydrogen. The free acidis then isolated from the reaction mixture by procedures known to theart. This procedure is also applicable to the production of FormulaXIX-to-XXVI PGE type free acids or Formula XXXV-to-XLII PGB type freeacids.

Formula-XLIV cyclic ketal and Formula-LI olefins wherein R₁₀ ishaloethyl as above defined are necessary as intermediates for this routeto the final PGE, PGF, PGA, and PGB type free acids. These Formula-XLIVand -LI haloethyl ester intermediates can be prepared by alkylation ofcyclic ketal XLIII (Chart E) or olefin L (Chart F), respectively, withthe appropriate Formula LX-to-LXVII alkylating agent wherein R₁₀ ishaloethyl as above defined. However, preferred routes to theFormula-XLIV and -LI haloethyl ester intermediates are shown in Charts Gand H.

In Charts G and H, R₂, R₃, R₄ Q, R₁₁, R₁₂, V, Z, and ˜ are as definedabove. Haloethyl represents ethyl substituted in the β-position with 3chloro, 2 or 3 bromo, or 1, 2, or 3 iodo, preferably --CH₂ CCl₃. R₁₇represents alkyl of one to 4 carbon atoms, inclusive, preferably methylor ethyl.

Compound LXVIII in Chart G is within the scope of compound XLIV in ChartE. Compound LXXIV in Chart H is within the scope of compound LI in ChartF. Ketones LXVIII and LXXIV are reduced to corresponding hydroxycompounds LXIX and LXXV, respectively, with a carbonyl reducing agent,e.g., sodium borohydride, as described above in discussion of Chart A.Then, hydroxy esters LXIX and LXXV are saponified by known procedures tohydroxy acids LXX and LXXVI, respectively. These two hydroxy acids aretransformed to keto haloethyl esters LXXIII and LXXIX, respectively, byoxidation of the hydroxy group to keto and esterification of thecarboxyl group to --COO-haloethyl. As shown in Charts G and H, these tworeactions are carried out in either order. However, it is preferred tooxidize first and then esterify. ##SPC40## ##SPC41##

Hydroxy acids LXX and LXXVI are oxidized to keto acids LXXII andLXXVIII, respectively, and hydroxy haloesters LXXI and LXXVII areoxidized to keto haloesters LXXIII and LXXIX, respectively, by reactionwith an oxidizing agent which does not attack other parts of thesemolecules, especially the cyclic ketal group of compounds LXX and LXXIor the ethylenic linkage of compounds LXXVI and LXXVII. An especiallyuseful reagent for this purpose is the Jones reagent, i.e., acidicchromic acid. Acetone is a suitable diluent for this purpose, and aslight excess of oxidant and temperatures at least as low as about 0°C., preferably about -10° to about -20° C. should be used. The oxidationproceeds rapidly and is usually complete in about 5 to about 30 minutes.Excess oxidant is destroyed, for example, by addition of a loweralkanol, advantageously isopropyl alcohol, and the aldehyde is isolatedby conventional methods, for example, by extraction with a suitablesolvent, e.g., diethyl ether. Other oxidizing agents can also be used.Examples are mixtures of chromium trioxide and pyridine or mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide. See, for example, J.Am. Chem. Soc. 87, 5661 (1965).

Haloethyl esters LXXI, LXXIII LXXVII, and LXXIX are prepared by reactingacids LXX, LXXII, LXXVI, and LXXVIII, respectively, with the appropriatehaloethanol, e.g., β,β,β-trichloroethanol, in the presence of acarbodiimide, e.g., dicyclohexylcarbodiimide, and a base, e.g.,pyridine, preferably in the presence of an inert liquid diluent, e.g.,dichloromethane, for several hours at about 25° C.

As described above, the alkylations of cyclic ketal XLIII to XLIV (ChartE) and olefin L to LI (Chart F) usually produce mixtures of alpha andbeta alkylation products with respect to the ##EQU93## moieties. Also asdescribed above, those two isomers lead to different final products,alpha leading to the PG type series, and beta leading to the 8-iso-PGtype series. If a compound in one or the other of those two series ispreferred, there are two methods for favoring production of thepreferred final product.

One of those methods involves isomerization of the final product ofFormulas XI to XVIII. Either the alpha isomer of a Formula XI-to-XVIIIcompound, ester or free acid, or the corresponding beta isomer ismaintained in an inert liquid diluent in the range 0° to 80° C. and inthe presence of a base characterized by its water solution having a pHbelow about 10 until a substantial amount of the isomer has beenisomerized to the other isomer, i.e., alpha to beta or beta to alpha.Preferred bases for this purpose are the alkali metal salts ofcarboxylic acids, especially alkanoic acids of 2 to 4 carbon atoms,e.g., sodium acetate. Examples of useful inert liquid diluents arealkanols of one to 4 carbon atoms, e.g., ethanol. This reaction at about25° takes about one to about 20 days. Apparently an equilibrium isestablished. The mixtures of the two isomers, alpha and beta, areseparated from the reaction mixture by known procedures, and then thetwo isomers are separated from each other by known procedures, forexample, chromatography, recrystallization, or a combination of those.The less preferred isomer is then subjected to the same isomerization toproduce more of the preferred isomer. In this manner, by repeatedisomerizations and separation, substantially all of the less preferredisomer of the Formula XI-to-XVIII compound is transformed to morepreferred isomer.

The second method for favoring production of a preferred FormulaXI-to-XVIII isomer involves any one of the keto intermediates ofFormulas XLIV, XLV, LI, or LII (Charts E and F). Either the alpha formor the beta form of one of those intermediates is transformed to amixture of both isomers by maintaining one or the other isomer, alpha orbeta, in an inert liquid diluent in the presence of a base and in range0° to 100° C. until a substantial amount of the starting isomer has beenisomerized to the other isomer. Preferred bases for this isomerizationare alkali metal amides, alkali metal alkoxides, alkali metal hydrides,and triarylmethyl alkyli metals. Especially preferred are alkali metaltert-alkoxides of 4 to 8 carbon atoms, e.g., potassium tert-butoxide.This reaction at about 25° C. proceeds rapidly (one minute to severalhours). Apparently an equilibrium mixture of both isomers is formed,starting with either isomer. The isomer mixtures in the equilibriummixture thus obtained are isolated by known procedures, and then the twoisomers are separated from each other by known procedures, for example,chromatography. The less preferred isomer is then subjected to the sameisomerization to produce more of the preferred isomer. In this manner,by repeated isomerizations and separations, substantially all of theless preferred isomer of any of these intermediates is transformed tothe more preferred isomer. Cyclic ketalketone intermediates of FormulaXLIV are preferred over the other intermediates for this isomerizationprocedure.

The novel 3-oxa and 4-oxa phenyl-substituted PGE, PGF, PGA and PGB typecompounds of Formula XI to XLII wherein R₃ is alkyl of one to 4 carbonatoms, inclusive, preferably methyl or ethyl, are preferred over thecorresponding 3-oxa and 4-oxa phenyl-substituted PGE, PGF, PGA and PGBtype compounds in which R₃ is hydrogen for the above-describedpharmacological purposes.

These 15-alkyl prostaglandin analogs are surprisingly and unexpectedlymore useful than the corresponding 15-hydrogen compounds for the reasonthat they are substantially more specific with regard to potency incausing prostaglandin-like biological responses, and have substantiallylonger duration of biological activity. For that reason, fewer andsmaller doses of these 15-alkyl prostaglandin analogs are needed toattain the desired pharmacological results.

Although the above-mentioned 15-alkyl compounds are produced by themethods outlined above in Charts A-F, the preferred methods are setforth in Chart I and J as follows.

In Chart I is shown the transformation of 15-alkyl PGF-type acids andalkyl esters to the corresponding PGE-type acids and alkyl esters byoxidation. For this purpose, an oxidizing agent is used whichselectively oxidizes secondary hydroxy groups to carbonyl groups in thepresence of carbon-carbon double bonds. Formula LXXX in Chart I includesoptically active compounds as shown and racemic compounds of thatformula and the mirror images thereof, and also the 15-epimers of bothof those, i.e., wherein the configuration at C-15 is R rather than S asshown. Also in Chart I, E, Q, R₁, R₂, and V are as defined above, andR₁₉ is alkyl of one to 4 carbon atoms. ##SPC42##

For the transformations of Chart I, the β-hydroxy isomers of reactantLXXX are preferred starting materials when the carboxyl side chain isalpha, although the corresponding α-hydroxy isomers are also useful forthis purpose.

Oxidation reagents useful for the transformation set forth in Chart Iare known to the art. An especially useful reagent for this purpose isthe Jones reagent, i.e., acidified chromic acid. See. J. Chem. Soc. 39(1946). A slight excess beyond the amount necessary to oxidize one ofthe secondary hydroxy groups of the Formula-LXXX reactant is used.Acetone is a suitable diluent for this purpose. Reaction temperatures atleast as low as about 0° C. should be used. Preferred reactiontemperatures are in the range -10° to -50° C. The oxidation proceedsrapidly and is usually complete in about 5 to 20 minutes. The excessoxidant is destroyed, for example by addition of a lower alkanol,advantageously, isopropyl alcohol, and the Formula-LXXXI PGE-typeproduct is isolated by conventional methods.

Examples of other oxidation reagents useful for the Chart Itransformations are silver carbonate on Celite (Chem. Commun. 1102(1969)), mixtures of chromium trioxide and pyridine (Tetrahedron Letters3363 (1968), J. Am. Chem. Soc. 75, 422 (1953), and Tetrahedron, 18, 1351(1962)), mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide(J. Am. Chem. Soc. 89, 5505 (1967)), and mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87,5661 (1965)).

The novel 15-alkyl 3-oxa and 4-oxa phenyl-substituted PGF.sub.α- andPGF.sub.β-type acids and esters of Formulas XIX to XXVI wherein R₃ isone to 4 carbon atoms, inclusive, are preferably prepared from thecorresponding 15-hydrogen compounds by the sequence of transformationsshown in Chart J, wherein Formulas LXXXII through LXXXVI, inclusive,include optically active and racemic S and R compounds of those formulasand the mirror images thereof. Also in Chart J, R₁₉ is alkyl of one to 4carbon atoms, inclusive, and E, Hal, Q, R₁, R₂, and V are as heretoforedefined; Q" in Formula LXXXIV is ##SPC43##

wherein T" is the same as T above except that, in R₉, --Si(G)₃ replaceshydrogen. Also in Chart J, G is alkyl of one to 4 carbon atoms,inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenylsubstituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbonatoms, inclusive, and R₁₄ is R₁ as defined above or silyl of the formula--Si--(G)₃ wherein G is as defined above. The various G's of a --Si(G)₃moiety are alike or different. For example, a --Si(G)₃ can betrimethylsilyl, dimethylphenylsilyl, or methylphenylbenzylsilyl.Examples of alkyl of one to 4 carbon atoms, inclusive, are methyl,ethyl, propyl, isopropyl, isobutyl, sec-butyl, and tert-butyl. Examplesof aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl,α-phenylethyl, 3-phenylpropyl, α-naphthylmethyl, and2-(β-naphthyl)ethyl. Examples of phenyl substituted with one or 2fluoro, chloro, or alkyl of one to 4 carbon atoms, inclusive, arep-chlorophenyl, m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl,p-tert-butylphenyl, 4-chloro-2-methyl-phenyl, and2,4-dichloro-3-methylphenyl.

In Chart J, the final PGF.sub.α and PGF.sub.β-type products are thoseencompassed by Formulas LXXXV and LXXXVI, respectively. ##SPC44##

The initial optically active or racemic reactants of Formula LXXXII inChart J. i.e., the 3-oxa and 4-oxa phenyl-substituted PGF₁ -, PGF₂ -,dehydro-PGF₂ -, and dihydro-PGF₁ -type compounds in their α and β forms,and their esters, are prepared by methods described herein. Thus,racemic 3-oxa and 4-oxa phenyl-substituted dihydro-PGF₁ .sub.α- and-PGF₁ .sub.β-type compounds, and their esters are prepared by catalytichydrogenation of the corresponding racemic 3-oxa and 4-oxaphenyl-substituted PGF₁ .sub.α or PGF₂ .sub.α, and PGF₁ .sub.β or PGF₂.sub.β type compounds, respectively, e.g. in the presence of 5%palladium-on-charcoal catalyst in ethyl acetate solution at 25° C. andone atmosphere pressure of hydrogen.

The heretofore-described acids and esters of Formula LXXXII aretransformed to the corresponding intermediate 15-dehydro acids andesters of Formula LXXXIII, by oxidation with reagents such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone, activated manganese dioxide,or nickel peroxide (see Fieser et al., "Reagents for Organic Synthesis,"John Wiley * Sons, Inc., New York, N.Y. pp. 215, 637, and 731).Alternatively, and especially for the Formula-LXXXII reactants wherein Eand V are --CH₂ CH₂ --, these oxidations are carried out by oxygenationin the presence of the 15-hydroxyprostaglandin dehydrogenase of swinelung (see Arkiv for Kemi 25, 293 (1966)). These reagents are usedaccording to procedures known in the art. See, for example, J. Biol.Chem. 239, 4097 (1964).

Referring againt to Chart J, the intermediate compounds of FormulaLXXXIII are transformed to silyl derivatives of Formula LXXXIV byprocedures known in the art. See, for example, Pierce, "Silylation ofOrganic Compounds," Pierce Chemical Co., Rockford, Ill. (1968). Bothhydroxy groups of the Formula-LXXXIII reactants are thereby transformedto --O--Si--(G)₃ moieties wherein G is as defined above, and sufficientof the silylating agent is used for that purpose according to knownprocedures. When R₁ in the Formula-LXXXIII intermediate is hydrogen, the--COOH moiety thereby defined is simultaneously transformed to--COO--Si--(G)₃, additional silylating agent being used for thispurpose. This latter transformation is aided by excess silylating agentand prolonged treatment. Likewise, when R₉ in T of the Formula-LXXXIIIintermediate is hydrogen, the phenolic hydroxyl thereby defined issimultaneously transformed to --O--Si(G)₃ in the silylation step. Q" inFormula LXXXIV, therefore is ##SPC45##

wherein T" is the same as T above except that, in R₉, --Si(G)₃ replaceshydrogen. When R₁ in Formula LXXXIII is alkyl, then R₁₄ in FormulaLXXXIV will also be alkyl. The necessary silylating agents for thesetransformations are known in the art or are prepared by methods known inthe art. See, for example, Post, "Silicones and Other Organic SiliconCompounds, " Reinhold Publishing Corp., New York, N.Y. (1949).

Referring again to Chart J the intermediate silyl compounds of FormulaLXXXIV are transformed to the final compounds of Formulas LXXXV andLXXXVI by first reacting the silyl compound with a Grignard reagent ofthe formula R₁₉ MgHal wherein R₁₉ is as defined above, and Hal ischloro, bromo, or iodo. For this purpose, it is preferred that Hal bebromo. This reaction is carried out by the usual procedure for Grignardreactions, using diethyl ether as a reaction solvent and saturatedaqueous ammonium chloride solution to hydrolyze the Grignard complex.The resulting disilyl, trisilyl, or tetrasilyl tertiary alcohol is thenhydrolyzed with water to remove the silyl groups. For this purpose, itis advantageous to use a mixture of water and sufficient of awater-miscible solvent, e.g., ethanol to give a homogenous reactionmixture. The hydrolysis is usually complete in 2 to 6 hours at 25° C.,and is preferably carried out in an atmosphere of an inert gas, e.g.,nitrogen or argon.

The mixture of 15-S and 15-R isomers obtained by this Grignard reactionand hydrolysis is separated by procedures known in the art forseparating mixtures of prostanoic acid derivatives, for example, bychromatography on neutral silica gel. In some instances, the lower alkylesters, especially the methyl esters of a pair of 15-S and 15-R isomersare more readily separated by silica gel chromatography than are thecorresponding acids. In those cases, it is advantageous to esterify themixture of acids as described below, separate the two esters, and then,if desired, saponify the esters by procedures known in the art forsaponification of prostaglandins F.

Although Formula-LXXXV and -LXXXVI compounds wherein E is --CH₂ CHR₄ --and V is W as defined above may be produced according to the processesof Chart J, it is preferred to produce those novel dihydro-PGF₁ analogsby hydrogenation of one of the corresponding unsaturated compounds,i.e., a compound of Formula LXXXV or LXXXVI wherein E is trans --CH=CR₄-- and V is either W, --CH=CH--Y, or --C.tbd.C--Y--, Y being definedabove. This hydrogenation is advantageously carried out catalytically,for example, in the presence of a 5% palladium-on-charcoal catalyst inethyl acetate solution at 25° C. and one atmosphere pressure ofhydrogen.

The novel 15-alkyl 3-oxa and 4-oxa phenyl-substituted PGA-type andPGB-type acids and esters of Formulas XXVII to XLII are prepared fromthe 15-alkyl 3-oxa and 4-oxa phenyl-substituted PGE compounds,heretofore described, by dehydrations and double bond migrationspreviously described, as shown in Chart A. Likewise the 15-alkylPGB-type compounds are prepared by contacting the 15-alkyl PGA-typecompounds with base. For the transformation of the 15-alkyl PGE-typecompounds to the 15-alkyl PGA-type compounds of this invention (ChartK), it is preferred that a dehydrating agent be used which removes thehydroxy group from the alicyclic ring in the presence of a hydroxy groupon a tertiary carbon atom. Formula LXXXVII as shown includes opticallyactive compounds and racemic compounds of that formula and the mirrorimages thereof, and also the 15-epimers of both of those. Any of theknown substantially neutral dehydrating agents is used for thesereactions. See Fieser et al., cited above. Preferred dehydrating agentsare mixtures of at least an equivalent amount of a carbodiimide and acatalytic amount of a copper (II) salt. Especially preferred aremixtures of at least an equivalent amount of dicyclohexylcarbodiimideand a catalytic amount of copper (II) chloride. An equivalent amount ofa carbodiimide means one mole of the carbodiimide for each mole of theFormula-LXXXVII reactant. To ensure completeness of the reaction, it isadvantageous to use an excess of the carbodiimide, i.e., 1.5 to 5 oreven more equivalents of the carbodiimide. ##SPC46##

The dehydration is advantageously carried out in the presence of aninert organic diluent which gives a homogeneous reaction mixture withrespect to the Formula-LXXXVII reactant and the carbodiimide. Diethylether is a suitable diluent. It is advantageous to carry out thedehydration in an atmosphere of an inert gas, e.g., nitrogen, helium, orargon. The time required for the dehydration will depend in part on thereaction temperature. With the reaction temperature in the range of 20°to 30° C., the dehydration usually takes place in about 40 to 60 hours.

The Formula-LXXXVIII product is isolated by methods known in the art,e.g., filtration of the reaction mixture and evaporation of thefiltrate. The product is then purified by methods known in the art,advantageously by chromatography on silica gel.

The final Formula XI-to-XLII compounds prepared by the processes of thisinvention, in free acid form, are transformed to pharmacologicallyacceptable salts by neutralization with appropriate amounts of thecorresponding inorganic or organic base, examples of which correspond tothe cations and amines listed above. These transformations are carriedout by a variety of procedures known in the art to be generally usefulfor the preparation of inorganic, i.e., metal or ammonium, salts, amineacid addition salts, and quaternary ammonium salts. The choice ofprocedure depends in part upon the solubility characteristics of theparticular salt to be prepared. In the case of the inorganic salts, itis usually suitable to dissolve the Formula XI-to-XLII acid in watercontaining the stoichiometric amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. For example,such use of sodium hydroxide, sodium carbonate, or sodium bicarbonategives a solution of the sodium salt. Evaporation of the water oraddition of a water-miscible solvent of moderate polarity, for example,a lower alkanol or a lower alkanone, gives the solid inorganic salt ifthat form is desired.

To produce an amine salt, the Formula XI-to-XLII acid is dissolved in asuitable solvent of either moderate or low polarity. Examples of theformer are ethanol, acetone, and ethyl acetate. Examples of the latterare diethyl ether and benzene. At least a stoichiometric amount of theamine corresponding to the desired cation is then added to thatsolution. If the resulting salt does not precipitate, it is usuallyobtained in solid form by addition of a miscible diluent of low polarityor by evaporation. If the amine is relatively volatile, any excess caneasily be removed by evaporation. It is preferred to use stoichiometricamounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe Formula XI-to-XLII acid with the stoichiometric amount of thecorresponding quaternary ammonium hydroxide in water solution, followedby evaporation of the water.

The final Formula XI-to-XLII acids or esters prepared by the processesof this invention are transformed to lower alkanoates by interaction ofthe Formula XI-to-XLII hydroxy compound with a carboxyacylating agent,preferably the anhydride of a lower alkanoic acid, i.e., an alkanoicacid of one to 8 carbon atoms, inclusive. For example, use of aceticanhydride gives the corresponding diacetate. Similar use of propionicanhydride, isobutyric anhydride, and hexanoic acid anhydride gives thecorresponding carboxyacylates.

The carboxyacylation is advantageously carried out by mixing the hydroxycompound and the acid anhydride, preferably in the presence of atertiary amine such as pyridine or triethylamine. A substantial excessof the anhydride is used, preferably about 10 to about 10,000 moles ofanhydride per mole of the hydroxy compound reactant. The excessanhydride serves as a reaction diluent and solvent. An inert organicdiluent, for example, dioxane, can also be added. It is preferred to useenough of the tertiary amine to neutralize the carboxylic acid producedby the reaction, as well as any free carboxyl groups present in thehydroxy compound reactant.

The carboxyacylation reaction is preferably carried out in the rangeabout 0° to about 100° C. The necessary reaction time will depend onsuch factors as the reaction temperature, and the nature of theanhydride and tertiary amine reactants. With acetic anhydride, pyridine,and a 25° C. reaction temperature, a 12 to 24-hour reaction time isused.

The carboxyacylated product is isolated from the reaction mixture byconventional methods. For example, the excess anhydride is decomposedwith water, and the resulting mixture acidified and then extracted witha solvent such as diethyl ether. The desired carboxyacylate is recoveredfrom the diethyl ether extract by evaporation. The carboxyacylate isthen purified by conventional methods, advantageously by chromatography.

By this procedure, the Formula XI-to-XVIII PGE type compounds aretransformed to dialkanoates, the Formula XIX-to-XXVI PGF type compoundsare transformed to trialkanoates, and the Formula XXVII-to-XLII PGA typeand PGB type compounds are transformed to monoalkanoates.

When a PGE type dialkanoate is transformed to a PGF type compound bycarbonyl reduction as shown in Chart A, a PGF type dialkanoate is formedand is used for the above-described purposes as such or is transformedto a trialkanoate by the above-described procedure. In the latter case,the third alkanoyloxy group can be the same as or different from the twoalkanolyoxy groups present before the carbonyl reduction.

Molecules of each of the compounds encompassed by Formulas XI to XLIIand, except for L and LVII, of each intermediate formula each have atleast one center of asymmetry, and each can exist in racemic form and ineither enantiomeric form, i.e., d and l. A formula accurately definingthe d form would be the mirror image of the formula which defined the lform. Both formulas are necessary to define accurately the correspondingracemic form. For convenience, the various formulas are to be construedas including racemic, d, and l compounds.

When an optically active (d or l) final compound is desired, that ismade by resolution of the racemic compound or by resolution of one ofthe asymmetric racemic intermediates. These resolutions are carried outby procedures known in the art. For example, when final compound XI toXLII is a free acid, the dl form thereof is resolved into the d and lforms by reacting said free acid by known general procedures with anoptically active base, e.g., brucine or strychnine, to give a mixture oftwo diastereoisomers which are separated by known general procedures,e.g., fractional crystallization, to give the separate diastereoisomericsalts. The optically active acid of Formula XI to XLII is then obtainedby treatment of the salt with an acid by known general procedures.Alternatively, the free acid form of olefin LI, cyclic ketal XLIV, orglycols XLV or LII is resolved into separate d and l forms and thenesterified and transformed further to the corresponding optically activeform of the final product XI to XLII as described above.

Alternatively, bicyclo ketone reactants XLV or LII, in exo or endo form,are transformed to ketals with an optically active 1,2-glycol, e.g.,D-(--)-2,3-butanediol, by reaction of said 1,2-glycol with theFormula-XLV or -LII compound in the presence of a strong acid, e.g.,p-toluenesulfonic acid. The resulting ketal is a mixture ofdiastereoisomers which is separated into the d and l diastereoisomers,each of which is then hydrolyzed with an acid, e.g., oxalic acid, to theoriginal keto compound, now in optically active form. These reactionsinvolving optically active glycols and ketals for resolution purposesare generally known in the art. See, for example, Chem. Ind. 1664 (1961)and J. Am. Chem. Soc. 84,2938 (1962). Dithiols may be used instead ofglycols.

The invention can be more fully understood by the following examples andpreparations:

All temperatures are in degrees centigrade.

Infrared absorption spectra are recorded on a Perkin-Elmer model 421infrared spectrophotometer. Except when specified otherwise, undiluted(neat) samples are used.

For all of the preparations and examples herein, the NMR spectra arerecorded on a Varian A-60 spectrophotometer on deuterochloroformsolutions with tetramethylsilane as an internal standard (downfield).

Mass spectra are recorded on an Atlas CH-4 mass spectrometer with a TO-4source (ionization voltage 70 ev).

The collection of chromatographic eluate fractions starts when theeluent front reaches the bottom of the column.

Preparation 1

Endo-bicyclo[3.1.0]hexan-3-ol-6-carboxylic acid Methyl Ester.

A mixture of endo-bicyclo[3.1.0]hex-2-ene-6-carboxylic acid methyl ester(103 g.) and anhydrous diethyl ether (650 ml.) is stirred under nitrogenand cooled at -5° C. A one molar solution (284 ml.) of diborane intetrahydrofuran is added dropwise during 30 minutes while keeping thetemperature below 0° C. The resulting mixture is then stirred andallowed to warm to 25° C. during 3 hours Evaporation under reducedpressure gives a residue which is dissolved in 650 ml. of anhydrousdiethyl ether. The solution is cooled to 0° C., and 3 normal aqueoussodium hydroxide solution (172 ml.) is added dropwise under nitrogen andwith vigorous stirring during 15 minutes, keeping the temperature at 0°to 5° C. Next, 30% aqueous hydrogen peroxide (94 ml.) is added dropwisewith stirring during 30 minutes at 0° to 5° C. The resulting mixture isstirred an hour while warming to 25° C. Then, 500 ml. of saturatedaqueous sodium chloride solution is added, and the diethyl ether layeris separated.The aqueous layer is washed with four 200-ml. portions ofethyl acetate, the washings being added to the diethyl ether layer,which is then washed with saturated aqueous sodium chloride solution,dried, and evaporated to give 115 g. of a residue. This residue isdistilled under reduced pressure to give 69 g. of a mixture of themethyl esters of endo-bicyclo[3.1.0]hexan-3-ol-6-carboxylic acid andendo-bicyclo[3.1.0]hexan-2-ol-6-carboxylic acid; b.p. 86°-95° C. at 0.5mm.

Preparation 2

Endo-bicyclo[3.1.0]hexan-3-ol-6-carboxylic Acid Methyl EsterTetrahydropyranyl Ether.

The 2-ol and 3-ol mixture (66 g.) obtained according to Preparation 1 in66 ml. of dihydropyran is stirred and cooled at 15°-20° C. duringaddition of 3 ml. of anhydrous diethyl ether saturated with hydrogenchloride. The temperature of the mixture is then kept in the range 20°to 30° C. for one hour with cooling, and is then kept at 25° for 15hours. Evaporation gives a residue which is distilled under reducedpressure to give 66 g. of a mixture of the methylesters-tetrahydropyranyl ethers ofendo-bicyclo[3.1.0]hexan-3-ol-6-carboxylic acid andendo-bicyclo[3.1.0]hexan-2-ol-6-carboxylic acid; b.p. 96°-104° C. at 0.1mm.

Preparation 3

Endo-6-hydroxymethylbicyclo[3.1.0]hexan-3-ol-3-tetrahydropyranyl Ether.

A solution of the mixture (69 g.) of products obtained according toPreparation 2 in 300 ml. of anhydrous diethyl ether is added dropwiseduring 45 minutes to a stirred and cooled mixture of lithium aluminumhydride (21 g.) in 1300 ml. of anhydrous diethyl ether under nitrogen.The resulting mixture is stirred 2 hours at 25° C., and is then cooledto 0° C. Ethyl acetate (71 ml.) is added, and the mixture is stirred 15minutes. Water (235 ml.) is then added, and the diethyl ether layer isseparated. The water layer is washed twice with diethyl ether and twicewith ethyl acetate. A solution of Rochelle salts is added to the aqueouslayer, which is then saturated with sodium chloride and extracted twicewith ethyl acetate. All diethyl ether and ethyl acetate solutions arecombined, washed with saturated aqueous sodium chloride solution, dried,and evaporated to give 61 g. of a mixture of the 3-tetrahydropyranylethers of endo-6-hydroxymethylbicyclo[3.1.0]hexane-3-ol andendo-6-hydroxymethylbicyclo[3.1.0]hexan-2-ol.

Preparation 4

Endo-bicyclo[3.1.0]hexan-3-ol-6-carboxaldehyde 3-tetrahydropyranylEther.

A solution of the mixture (34 g.) of products obtained according toPreparation 3 in 1000 ml. of acetone is cooled to -10° C. Jones reagent(75 ml. of a solution of 21 g. of chromic anhydride, 60 ml. of water,and 17 ml. of concentrated sulfuric acid), precooled to 0° C., is addeddropwise with stirring during 10 minutes at -10° C. After 10 minutes ofadditional stirring at -10° C., isopropyl alcohol (35 ml.) is addedduring 5 minutes, and stirring is continued for 10 minutes. The reactionmixture is then poured into 8 l. of an ice and water mixture. Theresulting mixture is extracted 6 times with dichloromethane. Thecombined extracts are washed with aqueous sodium bicarbonate solution,dried, and evaporated to give 27 g. of a mixture of thetetrahydropyranyl ethers ofendo-bicyclo[3.1.0]hexan-3-ol-6-carboxaldehyde andendo-bicyclo[3.1.0]hexan-2-ol-6 -carboxaldehyde.

Preparation 5

(3-Phenylpropyl)triphenylphosphonium Bromide.

A solution of 597.3 g. of 1-bromo-3-phenylpropane and 786 g. oftriphenylphosphine in 1,500 ml. of toluene is heated at reflux undernitrogen for 16 hours, then the mixture is cooled and the solid productis separated by filtration. The solid is then slurried with toluene in aWaring blender, separated by filtration, and dried for 18 hours at 70°C. under reduced pressure to give 1068 g. of(3-phenylpropyl)triphenylphosphonium bromide; m.p. 210.5°-211.5° C.

Preparation 6

4-Phenyl-1-butanol.

A solution of 200 g. of 4-phenylbutyric acid in 1500 ml. of anhydrousether is added with stirring to a suspension of 46.3 g. of lithiumaluminum hydride in 1,800 ml. of anhydrous ether at a rate sufficient tomaintain gentle reflux while the mixture is cooled in an ice bath.Fifteen minutes after the addition is complete the mixture is treatedcautiously, under nitrogen, with 93 ml. of water and then 74 ml. of 10%aqueous sodium hydroxide. The mixture is stirred about 18 hours at about25° C. and dried over sodium sulfate, filtered, and concentrated underreduced pressure to give 171 g. of 4-phenyl-1-butanol; infraredabsorption at 3250, 2980, 1610, 1060, 1030, 750 and 700 cm⁻ ¹ ; NMRpeaks at 7.30 (singlet), 3.61 (triplet), 2.65 (multiplet) and 2.75(singlet) δ.

Preparation 7

4-Phenyl-1-bromobutane.

Phosphorus tribromide (40.5 ml.) is added dropwise to 171 g. of4-phenyl-1-butanol with cooling to keep the temperature between 0° C.and -5° C. This mixture is allowed to stand 16 hours at 25° C. and ispoured into a mixture of ice and aqueous sodium bicarbonate. The mixtureis extracted with hexane and the extract is washed with water, aqueoussodium bicarbonate, brine, dried over sodium sulfate and concentratedunder reduced pressure to give 196 g. of crude 4-phenyl-1-bromobutane.This is distilled to give 145.2 g. of 4-phenyl-1-bromobutane, b.p.103°-103.5°/16 mm; NMR peaks at 7.19 (multiplet), 3.14 (triplet) and2.45 δ.

Preparation 8

(4-Phenylbutyl)triphenylphosphonium Bromide.

A solution of 145 g. of 4-phenyl-1-bromobutane and 179 g. oftriphenylphosphine in 350 ml. of toluene is heated at reflux undernitrogen for 16 hours. The mixture is then cooled slowly and ether isadded giving a precipitate of (4-phenylbutyl)triphenylphosphoniumbromide which is washed thoroughly with benzene/ether and dried 18 hoursat 50° C. under reduced pressure, 268 g., m.p. 139°-140° C.

EXAMPLE 1

Endo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one (Formula L: Qis ##SPC47##

R₃ and R₄ are hydrogen; and ˜ is endo).

A suspension of 314 g. of (3-phenylpropyl)triphenylphosphonium bromidein 3 l. of benzene is stirred at room temperature (25° C.) undernitrogen, and 400 ml. of 1.6 M butyllithium in hexane is added over a 20min. period. The mixture is heated at 35° C. for 30 minutes, then iscooled to -15° C. and a solution of 100 g. ofendo-bicyclo[3.1.0]-hexan-3-ol-6-carboxaldehyde 3-tetrahydropyranylehter in 200 ml. of benzene is added over a 30-min. period. This mixtureis heated at 70° C. for 2.5 hours, cooled, and filtered. The filtrate iswashed three times with water, dried over sodium sulfate, and evaporatedto give 170 g. of crudeendo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]-hexan-3-ol3-tetrahydropyranyl ether.

A solution of 340 g. (two runs) of this crudeendo-6-(cis-4-phenyl-1-butenyl)-bicyclo-[3.1.0]hexan-3-ol3-tetrahydropyranyl ether and 20 g. of oxalic acid in 3,600 ml. ofmethanol is heated at reflux for 3.5 hours. The mixture is cooled andthe methanol is evaporated under reduced pressure. The residue is mixedwith dichloromethane, and the dichloromethane solution is washed withaqueous sodium bicarbonate, dried over sodium sulfate, and evaporated togive 272 g. of theendo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-ol.

A solution of 93 g. of the aboveendo-6-(cis-4-phenyl-1-butenyl)bicyclo[3.1.0]hexan-3-ol in 2570 ml. ofacetone is cooled to -5° C. and 160 ml of Jones reagent is added over aperiod of 30 minutes while cooling to maintain a temperature of -5° C.The mixture is allowed to stand for 10 minutes longer; then 100 ml. ofisopropyl alcohol is added and the mixture is swirled for 5 min. Themixture is then diluted with 6 l. of water and extracted several timeswith dichloromethane. The organic layers are separated, washed withdilute hydrochloric acid, water, dilute aqueous sodium bicarbonate, andbrine, then are dried over sodium sulfate, combined and evaporated togive 83 g. of crudeendo-6-(cis-4-phenyl-1-butenyl)-bicyclo-[3.1.0]hexan-3-one.

Crude endo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one (162 g.,two runs) is dissolved in isomeric hexanes (Skellysolve B) andchromatographed over 5 kg. of silica gel wet-packed with Skellysolve B,eluting successively with 11 l. of Skellysolve B, 62 l. of 2.5% ethylacetate in Skellysolve B, and 32 l. of 5% ethyl acetate in SkellysolveB. The last 8 l. of the 2.5% ethyl acetate in Skellysolve B eluates andthe 32 l. of 5% ethyl acetate in Skellysolve B eluates are combined andevaporated to give 75.8 g. ofendo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one; infraredabsorption at 3000, 1750, 1610, 1500, 1455, 1405, 1265, 1150, 778, 750,and 702 cm⁻ ¹., N.M.R. peaks at 7.18 (singlet) and 4.75-6.0 (broadmultiplet) δ.

EXAMPLE 2

Endo-6-(cis-5-phenyl-1-pentenyl)-bicyclo[3.1.0]hexan-3-one. (Formula L:Q is ##SPC48##

R₃ and R₄ are hydrogen; and ˜ is endo).

A suspension of 242 g. of (4-phenylbutyl)-triphenylphosphonium bromidein 2.3 l. of dry benzene at 25° C. is stirred and 300 ml. of 1.6 Mbutyllithium in hexane is added over 15 minute period. The mixture isstirred at 30° C. for 1 hour, then is cooled to 10° C. and a solution of75 g. of endobicyclo[3.1.0]hexan-3-ol-6-carboxaldehyde3-tetrahydropyranyl ether in 200 ml. of benzene is added over a 15minute period. The mixture is heated at 65°-70° C. for 3 hours, cooledand filtered. The filtrate is washed with water and brine, dried oversodium sulfate, and evaporated under reduced pressure to give 117 g. ofcrude endo-6-(cis-5-phenyl-1-pentenyl)-bicyclo[3.1.0]hexan-3-oltetrahydropyranyl ether showing a single spot, R_(f) 0.75, on thin layerchromatography with silica gel plates developed with 20% ethyl acetatein cyclohexane.

A solution of 117 g. of the above crudeendo-6-(cis-5-phenyl-1-pentenyl)-bicyclo[3.1.0]hexan-3-oltetrahydropyranyl ether and 6 g. of oxalic acid in 2500 ml. of methanolis heated under reflux for 2.5 hours. The methanol is then removed bydistillation under reduced pressure and the residue is diluted withwater and extracted with dichloromethane. The dichloromethane extractsare combined, washed with aqueous sodium bicarbonate and brine, driedover sodium sulfate and evaporated under reduced pressure to give 95.7g. of crude endo-6-(cis-5-phenyl-1-pentenyl)bicyclo-[3.1.0]hexan-3-ol.The entire crude product is chromatographed over 1.5 g. of silica gelwet-packed with Skellysolve B, eluting successively with 5 l. ofSkellysolve B, 4 l. of 2.5%, 6 l. of 5%, 9 l. of 7.5%, 12 l. of 10%, 8l. of 15%, 10 l. of 20% and 10 l. of 30% ethyl acetate in Skellysolve B,taking 600 ml. fractions. The last fraction of 10% ethyl acetate inSkellysolve B, all the 15% and 20% ethyl acetate in Skellysolve Beluates, and the first 3 fractions of 30% ethyl acetate in Skellysolve Bare evaporated to give 60.5 g. of purifiedendo-6-(cis-5-phenyl-1-pentenyl)bicyclo-[3.1.0 ]hexan-3-ol.

A solution of 60.5 g. of the above purified alcohol in 1,600 ml. ofacetate is cooled to -10° C. and 103 ml. of Jones reagent is addeddropwise. After addition is complete the mixture is stirred for 10minutes at 0° C. and 65 ml. of isopropyl alcohol is added. The mixtureis poured into 8 l. of water and extracted several times withdichloromethane. The dichloromethane extracts are combined, washed withdilute hydrochloric acid, aqueous sodium bicarbonate and brine, driedover sodium sulfate and evaporated under reduced pressure to give 56 g.of crude endo-6-(cis-5-phenyl-1-pentenyl)-bicyclo[3.1.0]hexan-3-one. Thecrude ketone is slurried in Skellysolve B and chromatographed over 2,300g. of silica gel wet packed in Skellysolve B, eluting successively with6 l. of Skellysolve B, 16 l. of 2.5% ethyl acetate in Skellysolve B,then gradient elution with 5 l. of 2.5% and 5 l. of 5% ethyl acetate inSkellysolve B and finally 16 l. of 5% ethyl acetate in Skellysolve B,taking 625 ml. fractions. The last fraction of the gradient eluates andthe first 19 fractions of 5% ethyl acetate in Skellysolve B areconcentrated to give 23.6 g. ofendo-6-(cis-5-phenyl-1-pentenyl)bicyclo[3.1.0]hexan-3-one; infraredabsorption at 2980, 1745, 1600, 1490, 1450, 1400, 1260, 1145, 770, 750and 702 cm⁻ ¹., N.M.R. peaks at 7.17 (singlet), 6.0-5.4 (multiplet), and5.2- 4.7 (broad multiplet) δ.

Following the procedures of Examples 1 and 2, but using intermediatequarternary phosphonium halides prepared as in Preparation 5 fromα-bromotoluene, (2-bromoethyl)benzene, (5-chloropentyl)benzene,(6-bromohexyl)benzene, and (7-iodoheptyl)benzene in place of1-bromo-3-phenylpropane, there are obtained the 2-phenyl-1-ethenyl,3-phenyl-1-propenyl, 6-phenyl-1-hexenyl, 7-phenyl-1-heptenyl, and8-phenyl-1-octenyl compounds corresponding to the products of Examples 1and 2.

Also following the procedures of Examples 1 and 2, but usingintermediate quaternary phosphonium halides prepared as in Preparation 5from (1-chloroethyl)benzene, (1-bromopropyl)benzene,(2-bromopropyl)benzene, (3-chloropentyl)benzene, (4-bromopentyl)benzene,(6-bromononyl)benzene and (7-bromononyl)benzene in place of1-bromo-3-phenylpropane, there are obtained the2-methyl-2-phenyl-1-ethenyl, 2-ethyl-2-phenyl-1-ethenyl,2-methyl-3-phenyl-1-propenyl, 2-ethyl-4-phenyl-1-butenyl,2-methyl-5-phenyl-1-pentenyl, 2-propyl-7-phenyl-1-heptenyl, and2-ethyl-8-phenyl-1-octenyl compounds corresponding to the products ofExamples 1 and 2.

Also following the procedures of Examples 1 and 2, but usingintermediate quarternary phosphonium halides prepared as in Preparation5 from (2-bromo-1-fluoroethyl)benzene, (2-bromo-1-fluoropropyl)benzene,(2-chloro-1-fluoro-1-methylpropyl)benzene,(5-bromo-4-fluoropentyl)benzene, (7-iodo-6-fluoropentyl)benzene,(4-bromo-3,3-difluorobutyl)benzene, and(6-bromo-5,5-difluorohexyl)benzene in place of 1-bromo-3-phenylpropane,there are obtained the 3-fluoro-3-phenyl-1-propenyl,3-fluoro-1-methyl-3-phenyl-1-propenyl,3-fluoro-2,3-dimethyl-3-phenyl-1-propenyl, 3-fluoro-6-phenyl-1-hexenyl,3-fluoro-8-phenyl-1-octenyl, 3,3-difluoro-5-phenyl-1-pentenyl, and3,3-difluoro-7-phenyl-1-heptenyl compounds corresponding to the productsof Examples 1 and 2.

Also following the procedures of Examples 1 and 2, but usingintermediate quaternary phosphonium halides prepared as in Preparation 5from α-bromo-m-xylene, α-chloro-p-ethyltoluene, α-bromo-p-chlorotoluene,α'-chloro-α,α,α-trifluoro-m-xylene, 1-(2-bromoethyl)-4-fluorobenzene,1-(5-bromopentyl)2-chlorobenzene,4-(3-iodopropyl)-1,2-dimethyoxybenzene, and1-(3-bromohexyl)-2,4,6-trimethylbenzene in place of1-bromo-3-phenylpropane, there are obtained the2-(2-methylphenyl)-1-ethenyl, 2-(4-ethylphenyl)-1-ethenyl,2-(4-chlorophenyl)-1-ethenyl, 2-[3-(trifluoromethyl)phenyl]-1-ethenyl,3-(4-fluoro-phenyl)-1-propenyl, 6-(2-chlorophenyl)-1-hexenyl,4-(3,4-dimethoxyphenyl)-1-butenyl, and7-(2,4,6-trimethylphenyl)-1-heptenyl compounds corresponding to theproducts of Examples 1 and 2.

Also following the procedures of Example 1, but using quaternarytriphenyl phosphonium halides prepared from other primary and secondaryhalides of the formula ##SPC49##

wherein Hal, R₃, --C_(t) H_(2t) --, T and s are as defined above inplace of 1-bromo-3-phenylpropane, there are obtained compoundscorresponding to the products of Example 1 with ##SPC50##

in place of the 4-phenyl-1-butenyl moiety.

Also following the procedure of Example 1, but usingbicyclo[3.1.0]hexane reactants with ##EQU94## in place of ##EQU95##wherein R₄ is as defined above, there are obtained compoundscorresponding to the products of Example 1 with ##SPC51##

in place of the 4-phenyl-1-butenyl moiety.

Also following the procedures of Examples 1 and 2 but usingexo-bicyclo[3.1.0]hexane reactants in place of each of the endoreactants defined in Examples 1 and 2 and above, the exo products areobtained corresponding to the endo products of Examples 1 and 2 andabove.

By the above-described procedures, each of the reactants encompassed byFormula L, above, is prepared.

EXAMPLE 3

Ethyl7-[Endo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxaheptanoate(Formula LI: Q is ##SPC52##

R₂, r₃, and R₄ are hydrogen; R₁₀ is ethyl; Z is --(CH₂)₃ --O--CH₂ --;and ˜ is endo and alpha).

To a solution ofendo-6-(cis-4-phenyl-1-butenyl)bicyclo[3.1.0]hexan-3-one (11.3 g.),ethyl 7-iodo-3-oxaheptanoate (41 g.), and dicyclohexyl-18-crown-6 [J.Am. Chem. Soc. 89, 7017 (1967)], (4.6 g.) in 270 ml. of tetrahydrofuranfreshly distilled from lithium aluminum hydride is added, at roomtemperature with stirring under nitrogen, a solution of potassiumt-butoxide (6.7 g.) in 550 ml. of tetrahydrofuran (treated as above)over a period of 50 min. Three minutes after the addition of thebutoxide solution is completed, 50 ml. of 5% aqueous hydrochloric acidis added, then 5 ml. of pyridine. The mixture is then concentrated underreduced pressure by heating it in a water bath at 35° C. until most ofthe tetrahydrofuran is removed. The aqueous residue is extracted withdichloromethane and the extract is washed with ice-cold dilutehydrochloric acid, water, dilute aqueous sodium thiosulfate, and brine,then dried over sodium sulfate and concentrated under reduced pressureto give an oil. The oil is dissolved in 100 ml. of ethylacetate-cyclohexane (10:90) and chromatographed over 2 kg. of silica gelwet-packed in ethyl acetate-cyclohexane (10:90), eluting with 8 l. of10% and 7 l. of 20% ethyl acetate in cyclohexane, taking 200-ml.fractions. Fractions 50-65 are evaporated under reduced pressure to give7.2 g. of the desired ethyl7-[endo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxaheptanoate;mass spectral peaks at 384, 342 and 293.

Following the procedure of Example 3 but using a larger amount ofpotassium tert-butoxide (16 g.) and maintaining the reaction mixture for8 hours at 25° C. before addition of hydrochloric acid, a product isobtained which contains substantial amounts of both the above-described2α-yl isomer and the corresponding 2β-yl isomer. These isomers areseparated by the above-described silica gel chromatography.

EXAMPLE 4

Ethyl2,2-Dimethyl-7-[exo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2.alpha.-yl]-3-oxaheptanoate(Formula LI: Q is ##SPC53##

R₂, r₃, and R₄ are hydrogen; R₁₀ is ethyl; Z is --(CH₂)₃ --O--C(CH₃)₂--; ˜ is endo and alpha).

Following the procedures of Example 3 but substituting ethyl2,2-dimethyl-7-iodo-3-oxaheptanoate for ethyl 7-iodo-3-oxaheptanoate,and substitutingexo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one forendo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one, andsubstituting ethyl acetate for dichloromethane, there are obtained ethyl2,2-dimethyl7-[exo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxaheptanoateand the corresponding -2β-yl isomer.

Following the procedures of Examples 3 and 4, but using in place of thebicyclo[3.1.0]hexane reactant, each of endo and exo forms of the variousFormula-L bicyclo[3.1.0]hexane reactants whose preparation is describedfollowing Example 2, for example, Formula-L bicyclo compounds wherein Q,R₃, R₄, and ˜ are as defined above, those being prepared as describedabove, there are obtained alpha and beta exo and endo Formula-LIcompounds corresponding to the products of Example 3 with one of these Qmoieties in place of the ##SPC54##

moiety (the Q portion of those products). Accordingly, using Formula-Lbicyclo compounds wherein --C_(t) H_(2t) represents alkylene substitutedwith one or 2 fluoro, for example the bicyclo compound prepared by theprocedures of Preparation 5 and Example 1 from(2-bromo-1-fluoroethyl)benzene, (5-bromo-4-fluoropentyl)benzene, and(6-bromo-5,5-difluorohexyl)benzene there are obtained Formula-LIcompounds corresponding to the products of Examples 3 and 4 wherein--C_(t) H_(2t) represents alkylene substituted with one or 2 fluoro.Accordingly, using the Formula-L bicyclo compounds wherein (T)_(s) onthe phenyl ring is alkyl of one to 4 carbon atoms, inclusive, fluoro,chloro, trifluoromethyl, or OR₉ wherein R₉ is hydrogen, alkyl of one to4 carbon atoms, inclusive, or tetrahydropyranyl, and s is one, 2, or 3,for example Formula-L bicyclo compounds wherein (T)_(s) is 2-methyl,2,4,6-trimethyl,2-chloro,3-trifluoromethyl, or 3,4-dimethoxy, there areobtained Formula-LI compounds corresponding to the products of Examples3 and 4. As for Example 3, with excess base and a longer reaction time,these alternative products contain substantial amounts of thecorresponding beta isomer which is separated from the alpha isomer asdescribed above.

Also following the procedure of Examples 3 and 4, but using in place ofthe iodo alkylating agents of those Examples, ethyl7-iodo-4-oxaheptanoate, ethyl 7-iodo-3-oxa-5-heptynoate, and ethyl8-iodo-4-oxa-6-octynoate, there are obtained alpha and beta exo and endoFormula-LI compounds corresponding to the products of Examples 3 and 4with --(CH₂)₃ OCH₂ CH₂ COOEt, --CH₂ C.tbd.CCH₂ OCH₂ COOEt, and --CH₂C.tbd.CCH₂ OCH₂ CH₂ COOEt, respectively, wherein Et is ethyl, in placeof the --(CH₂)₄ OCH₂ COOEt and --CH₂)₄ OC(CH₃)₂ COOEt moieties of theproducts of Examples 3 and 4. As described above, both alpha and betaproducts are so obtained. In the same manner but using, according toExamples 3 and 4, other esters of the Examples 3 and 4 alkylating agentsand of the other above-mentioned alkylating agents within the scope ofR₁₀ as above-defined, e.g., the methyl, isopropyl, tert-butyl, octyl,cyclohexyl, benzyl, and phenyl esters, there are obtained thecorresponding esters of the alpha and beta bicyclo[3.1.0]hexanealkylation products.

Also following the procedure of Examples 3 and 4 but using incombination each of the above-described alternative Formula-Lbicyclo[3.1.0]hexane reactants and each of the above-describedalternative omega-halo alkylation reactants, there are obtainedFormula-LI compounds corresponding to the products of Examples 3 and 4but different therefrom with respect to both the carboxylate-terminatedside chain and the side chain attached to the cyclopropane ring of theproduct.

Also following the procedure of Examples 3 and 4, but using in place ofthe iodo alkylating agents of those Examples, each of the otheralkylating agents within the scope of ##EQU96## as above defined, i.e.,alkylating agents of Formulas LX, LXI, LXII, and LXIII asabove-described, there are obtained alpha and beta exo and endoFormula-LI compounds corresponding to the products of Examples 3 and 4with each of the other ##EQU97## side chains in place of the --(CH₂)₄OCH₂ COOEt and --(CH₂)₄ OC(CH₃)₂ COOEt side chains of the Examples 3 and4 products. For example, using as alkylating agents in the Example 3 and4 procedure, I(CH₂)₄ OCH(CH₃)COOEt, ICH(CH₃)--(CH₂)₃ OCH₂ COOEt, I(CH₂)₃OCH₂ COOEt, I(CH₂)₅ OCH₂ COOEt, ICH₂ CH(CH₃)CH₂ CH₂ OCH₂ COOEt, ICH₂ CH₂C(CH₂ CH₃)₂ CH₂ OCH₂ COOEt, I(CH₂)₃ C(CH₃)₂ OCH₂ COOEt, I(CH₂)₃ OCH₂ CH₂COOEt, I(CH₂)₂ OCH₂ CH₂ COOEt, I(CH₂)₄ OCH₂ CH₂ COOEt, I(CH₂)₃OCH(CH₃)CH₂ COOEt, I(CH₂)₃ OC(CH₃)₂ CH₂ COOEt, I(CH₂)₃ OCH₂ C(CH₃)₂COOEt, ICH(CH₃)CH₂ CH₂ OCH₂ CH₂ COOEt, ICH₂ CH(CH₃)CH₂ OCH₂ CH₂ COOEt,ICH₂ CH₂ C(CH₃)₂ OCH₂ CH₂ COOEt, ICH₂ C(CH₂ CH₃)₂ CH₂ OCH₂ CH₂ COOEt,ICH₂ C.tbd.CCH₂ OCH₂ COOEt, ICH(CH₃)C.tbd.CCH₂ OCH₂ COOEt, ICH₂C.tbd.CCH₂ CH₂ OCH₂ COOEt, ICH₂ C.tbd.CCH₂ OCH(CH₃)COOEt, ICH₂C.tbd.CCH₂ OC(CH₃)₂ COOEt, ICH₂ C.tbd.CCH(CH₃)OCH₂ COOEt, ICH₂C.tbd.CC(CH₃)₂ OCH₂ COOEt, ICH₂ C.tbd.C-CH₂ OCH₂ CH₂ COOEt,ICH(CH₃)C.tbd.CCH₂ OCH₂ CH₂ COOEt, ICH₂ C.tbd.CCH₂ CH₂ OCH₂ CH₂ COOEt,ICH₂ C.tbd.CCH₂ OCH(CH₃)CH₂ COOEt, ICH₂ C.tbd.CCH₂ OC(CH₃)₂ CH₂ COOEt,ICH₂ C.tbd.CCH(CH₃)OCH₂ CH₂ COOEt, ICH₂ C.tbd.CC(CH₃)₂ OCH₂ CH₂ COOEt,ICH₂ C.tbd.CCH₂ OCH₂ C(CH₃)₂ COOEt there are obtained exo and endo alphaand beta alkylated bicyclo[3.1.0]hexanes each having acarboxylate-terminated side chain corresponding to one of the abovespecific omega-iodo alkylating agents. For example, the side chain willbe alpha or beta --(CH₂)₄ OCH(CH₃)COOEt when the alkylating agent isI(CH₂)₄ OCH(CH₃)COOEt.

Also following the procedure of Examples 3 and 4, but using incombination each of the alternative alkylating agents within the scopeof ##EQU98## including the specific examples of those just mentioned,and each of the above-described Formula-L alternativebicyclo[3.1.0]hexane reactants, there are obtained Formula-LI exo andendo alpha and beta compounds corresponding to the products of Examples3 and 4 but different therefrom with respect to both thecarboxylate-terminated side chain and the side chain attached to thecyclopropane ring of the product. In the same manner, alternativealkylating agents within the scope of ##EQU99## wherein R₁₀ is otherthan ethyl, e.g., methyl, isopropyl, tert-butyl, octyl, cyclohexyl,benzyl, phenyl, and β,β,β-trichloroethyl are used.

EXAMPLE 5

Ethyl7-[Endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxaheptanoate(Formula LII: Q is ##SPC55##

R₂, r₃, and R₄ are hydrogen; R₁₀ is ethyl; Z is --(CH₂)₃ --O--CH₂ --;and ˜ is endo and alpha).

A solution of potassium chlorate (12.4 g.) in 150 ml. of water is addedto a solution of ethyl7-[endo-6-[cis-4-phenyl-1-butenyl]-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxaheptanoate(15.9 g. ) in 365 ml. of tetrahydrofuran at 50° C., then 0.73 g. ofosmium tetroxide is added and the mixture is stirred at 50° C. for 2.25hours., then concentrated under reduced pressure until most of thetetrahydrofuran is removed. The aqueous residue is extracted withdichloromethane and the extract is washed with water and then brine,dried over sodium sulfate, and concentrated under reduced pressure togive an oil. The oil is chromatographed over 2 kg. of silica gelwet-packed with ethyl acetate-cyclohexane (1:1 vol/vol), eluting with 6l. of 2:1 and 4 l. of 3:1 ethyl acetate-cyclohexane and 5.6 l. of ethylacetate, taking 200 ml. eluate fractions, then one 1000 ml. ethylacetate fraction. Fractions 48-78 plus the 1000 ml. fraction areconcentrated under reduced pressure to give 12.5 g. of the desired ethyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxo-bicyclo[3.1.0]-hex-2α-yl]-3-oxaheptanoate as a mixture of erythro and threo glycols; mass spectralpeaks at 418, 400 and 283; NMR peaks at 7.22, 4.37-4.02, 3.61-3.39,3.08-2.59, 2.33, 1.66-1.42, and 1.36-1.13 δ.

Following the procedure of Example 5 but using the hex-2β-yl isomer inplace of the hex-2α-yl isomer of the bicyclo reactant ethyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxo-bicyclo[3.1.0]hex-2β-yl]-3-oxaheptanoateis obtained.

Also following the procedure of Example 5, each of the Formula-LI exoand endo, alpha and beta, saturated and acetylenic bicyclo[3.1.0]hexaneolefinic esters defined above after Examples 3 and 4 is oxidized tomixtures of the corresponding isomeric Formula-LII dihydroxy compounds.

EXAMPLE 6

dl-3-Oxa-17-phenyl118,19,20-trinor-PGE₁ Ethyl Ester, anddl-15-Epi-3-oxa-17-phenyl-18,19,20-trinor-PGE₁, Ethyl Ester (Formula XI:C_(n) H_(2n) is --(CH₂)₃ --; C_(t) H_(2t) is ethylene; R₁ is ethyl; R₂,R₃, R₄, R₅, and R₆ are hydrogen; s is zero; and ˜ is alpha).

The steps shown in Chart F are followed. A solution of ethyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxaheptanoate(mixture of isomeric glycols) (12.4 g.) in 150 ml. of dry pyridine iscooled to -5° C. and to it is added 15 ml. of methanesulfonyl chlorideat such a rate that the reaction temperature does not exceed 0° C. Themixture is stirred for 2.5 hours at 0° C. following addition ofmethanesulfonyl chloride. Then water is added dropwise, with continuedcooling to keep the temperature below 5° C., to decompose excessmethanesulfonyl chloride. The mixture is diluted with 300 ml. of icewater and extracted with dichloromethane. The extract is washedsuccessively with ice-cold dilute hydrochloric acid, dilute aqueoussodium bicarbonate, and brine, then dried over sodium sulfate andevaporated under reduced pressure to give an oil. The oil is dissolvedin 50 ml. of 3:1 (vol./vol.) ethyl acetate-cyclohexane andchromatographed over 1.5 kg. of silica gel wet-packed in 3:1 ethylacetate-cyclohexane, eluting with 1.5 l. of 3:1 ethylacetate-cyclohexane, 3 l. of ethyl acetate, 3 l. of 2%, 2.4 l. of 5% and2 l. of 10% ethyl alcohol in ethyl acetate, taking 150-ml. fractions.Fractions 46-63 are evaporated under reduced pressure to give 1.6 g. ofthe desired dl-15-epi-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester;mass spectral peaks at 400 and 382. NMR peaks at 7.22, 5.78-5.63,4.35-3.99 (multiplet), 3.62-3.37, 2.97-2.60 (multiplet), 1.66-1.42,1.36-1.13 (multiplet) δ.

Fractions 58-68 (5% ethyl alcohol in ethyl acetate) and the 10% ethylfractions are combined and evaporated to givedl-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester mixed with the15-epi isomer. This is rechromatographed as above to give 1.41 g. of thedesired dl-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester; massspectral peaks at 400 and 382. NMR peaks at 7.22, 5.73-5.56, 4.35-4.02(multiplet), 3.53-3.33, 2.82-2.39 (multiplet), 2.03-1.76 (multiplet),1.66-1.42, and 1.36-1.13 (multiplet) δ.

Following the procedures of Example 6, each of the Formula-LIIendo-1,2-dihydroxy-3-oxa esters and endo-1,2-dihydroxy-4-oxa estersfollowing Example 5 is transformed to the correspondingendo-1,2-dimesyloxy-3(or -4)- oxa ester, and thence to the correspondingPGE type compound or its isomers.

Also following the procedures of Example 6, each of the Formula-LIIexo-1,2-dihydroxy-3-(or -4)-oxa esters corresponding to the aboveendo-1,2-dihydroxy-3(or -4)-oxa esters is transformed to thecorresponding exo-1,2-dimesyloxy-3(or -4)-oxa ester, and thence to thecorresponding PGE type compound or its isomers.

By the above-outlined procedures, following the steps of Chart F, thereare obtained the specific PGE type esters represented by Figures XI,XII, XV, and XVI, e.g. the esters of 3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGE₁ ;

3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGE₁ ;

5,6-dehydro-3-oxa (or 4-oxa)-17-phenyl-18,19,20-trinor-PGE₂ ;

5,6-dehydro-3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGE₂ ; includingtheir 8-iso and 15-epi forms.

For example, β,β,β-trichloroethyl2,2,3,3-tetramethyl-7-[endo-6-(3-fluoro-3-phenyl-1-propenyl)-3-oxo-bicyclo[3.1.0]-hex-2α-yl]-7-methyl-4-oxaheptanoateyields β,β,β-trichloroethyl2,2,3,3-tetramethyl-7-[endo-6-(3-fluoro-1,2-dihydroxy-3-phenyl-propyl)-3-oxo-bicyclo[3.1.0]hex-2α-yl]-4-oxaheptanoatein its isomeric forms, and thence the corresponding bis(mesylate) andthence the corresponding PGE₁ type compound and its 15-epimer, asrepresented by the following formulas: ##SPC56##

Likewise, methyl2,2-dimethyl-7-{exo-6-[1,2-dimethyl-5-(4-methoxyphenyl)-1-pentenyl]-3-oxo-bicyclo[3.1.0]hex-2β-yl}-3-oxa-5-heptynoateyields methyl2,2-dimethyl-7-{exo-6-[1,2-dihydroxy-5-(4-methoxyphenyl)-1-pentane]-3-oxo-bicyclo[3.1.0]hex-2β-yl}-3-oxa-5-heptynoatein its isomeric forms, and thence the corresponding bis(mesylate) andthence the corresponding dehydro-PGE₂ type compound and its 15-epimers,as represented by the following formulas: ##SPC57##

Also following the procedure of Example 6, but replacing methanesulfonylchloride with an alkanesulfonyl chloride or bromide or with analkanesulfonic acid anhydride, wherein the alkane moiety contains 2 to 5carbon atoms, inclusive, there is obtained from each dihydroxy compoundthe corresponding bis(sulfonic acid) esters encompassed by Formula LIII.

In each of the above transformations in Example 6, the monosulfonic acidester is also obtained as a byproduct, which is reacted with additionalalkanesulfonyl halide or alkanesulfonic acid anhydride to give thecorresponding bis(sulfonic acid) ester and thence recycled back toadditional Formula-LIV product.

For satisfactory yields of the bis-sulfonic acid ester, R₁₀ is nothydrogen. Those intermediate compounds in which R₁₀ is haloethyl, e.g.,β,β,β-trichloroethyl, are especially useful in the sequence of reactionsleading to the acid form of the prostaglandin-like products. Each of theexo and endo, alpha and beta, saturated and unsaturated 3-oxa or 4-oxaphenyl-substituted bis(alkanesulfonic acid) esters is transformed to thecorresponding 3-oxa or 4-oxa phenyl-substituted PGE type compoundencompassed by Formula LIV.

EXAMPLE 7

dl-3-Oxa-17-phenyl-18,19,20-trinor-PGE₁ (Formula XI: C_(n) H_(2n) is--(CH₂)₃ --; C_(t) H_(2t) is ethylene; R₁, R₂, R₃, R₄, R₅, and R₆ arehydrogen; s is zero; and ˜ is alpha).

Zinc dust (420 mg.) is added to a solution containing3-oxa-17-phenyl-18,19,20-trinor-PGE₁ β,β,β-trichloroethyl ester (100mg.) in 5 ml. of a mixture of acetic acid and water (9:1 v/v). Thismixture is stirred under nitrogen 2 hours at 25° C. Ethyl acetate (4volumes) is then added, followed by addition of one normal hydrochloricacid (one volume). The ethyl acetate later is separated, washed withwater and then with saturated aqueous sodium chloride solution, dried,and evaporated. The residue is chromatographed on 15 g. of acid-washedsilica gel (Silicar CC4), being eluted with 100 ml. of 50%, 100 ml. of80%, and 200 ml. of 100% ethyl acetate in Skellysolve B, collecting20-ml. fractions. The fractions containingdl-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ and no starting material ordehydration products as shown by TLC are combined and evaporated to givedl-3-oxa-17-phenyl-18,19,20-trinor-PGE₁.

Following the procedure of Example 7, each of the β,β,β-tribromoethyl,-triiodoethyl, β,β-dibromoethyl, -diiodoethyl, and the β-iodoethylesters of 3-oxa-17-phenyl-18,19,20-trinor-PGE₁ is converted to the freeacid of 3-oxa-17-phenyl-18,19,20-trinor-PGE₁ by reaction with zinc dustand acetic acid. Likewise, the corresponding 4-oxa compounds areconverted to 4-oxa-17-phenyl-18,19,20-trinor-PGE₁.

Following the procedure of Example 7, the β,β,β-trichloroethyl ester of3-oxa-18-phenyl-19,20-dinor-PGE₂ following Example 23 below is convertedto the respective free acid compound using zinc dust with eitherpropionic, butyric, pentanoic, or hexanoic acid instead of acetic acid.Likewise the corresponding 4-oxa compounds are converted to4-oxa-18-phenyl-19,20-dinor-PGE₂.

Following the procedure of Example 7, the β,β,β-trichloroethyl ester ofeach of the PGE, PGF, PGA and PGB type compounds represented by FormulasXI-XLII in their various structural configurations and optical isomersis treated with zinc dust and acetic acid to obtain the correspondingfree acid form of the compound. The esters are prepared by theprocedures disclosed herein, using as intermediates Formula-XLIV cyclicketals or Formula-LI olefins wherein R₁₀ is haloethyl, e.g.,β,β,β-trichloroethyl. These intermediates are prepared either byalkylation of the respective Formula-XLIII cyclic ketal (Chart E) ofFormula-L olefin (Chart F) with the appropriate alkylating agent whereinR₁₀ is haloethyl, or by the transformation of the alkylated cyclic ketalor olefin by the steps shown in Charts G and H using proceduresdisclosed herein, yielding intermediates LXXI, LXXIII, LXXVII, LXXXIX.

EXAMPLE 8

dl-3-Oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α Ethyl Ester anddl-3-Oxa-17-phenyl-18,19,20trinor-PGF₁.sub.β Ethyl Ester (Formula XIX:C_(n) H_(2n) is -(CH₂)₃ -; C_(t) H_(2t) is ethylene; R₁ is ethyl; R₂,R₃, R₄, R₅, and R₆ are hydrogen; s is zero; and ˜ is alpha or beta).

A solution of sodium borohydride (300 mg.) in 6 ml. of ice-cold methanolis added to a solution of dl-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethylester (650 mg.) in 30 ml. of methanol at -5° C. the mixture is stirredfor 0.5 hours at 0° C. and 5 ml. of acetone is added, after which themixture is stirred for 5 minutes and made slightly acid with aceticacid. The mixture is evaporated under reduced pressure until most of themethanol and acetone are removed, then the residue is extracted withdichloromethane. The extract is washed with water, dilute aqueous sodiumbicarbonate, and brine, then dried over sodium sulfate and evaporatedunder reduced pressure to give a residue (690 mg.). This residue ischromatographed over 105 g. of silica-gel wet-packed in ethyl acetate,eluting with 750 ml. of 2%, 500 ml. of 4%, 625 ml. of 7.5% and 875 ml.of 10% ethanol in ethyl acetate, taking 25 ml. fractions. Fractions 54-71 are evaporated to a residue, which is recrystallized fromether-pentane to give 140 mg. of the desireddl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.β ethyl ester, m.p. 76°-80°C.; mass spectral peaks at 402, 384, and 366; NMR peaks at 7.22,5.63-5.41, 4.35-3.97 (multiplet), 3.70, 3.49- 3.30, 2.78- 2.53(multiplet), 1.66- 1.42, and 1.36- 1.13 (multiplet) δ.

Fractions 26-53 are evaporated under reduced pressure and the residue isrechromatographed as above to give 139 mg. of the desireddl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α ethyl ester as an oil;mass spectral peaks at 420, 402, 384 and 366; NMR peaks at 7.22,5.60-5.42, 4.35-3.97 (multiplet), 3.70, 3.49-3.23, 2.80-2.53(multiplet), 1.66-1.42, and 1.36-1.13 (multiplet) δ.

Following the procedure of Example 8,4-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester is transformed to4-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β ethyl esters.Likewise, 3-oxa-18-phenyl-19,20-dinor-PGE₁ ethyl ester and4-oxa-18-phenyl-19,20-dinor-PGE₁ ethyl ester are transformed to thecorresponding PGF₁.sub.α and PGF₁.sub.β type ethyl esters.

EXAMPLE 9

dl-3-Oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α anddl-3-Oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.β (Formula XIX: C_(n) H_(2n)is -(CH₂)₃ -; C_(t) H_(2t) is ethylene: R₁, R₂, R₃, R₄, R₅, and R₆ arehydrogen; s is zero; and ˜ is alpha or beta).

A solution of 146 mg. of dl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.αethyl ester in a mixture of 4.5 ml. of methanol and 1.5 ml. of water iscooled to 5° C. and 0.6 ml. of 45% aqueous potassium hydroxide is added.The mixture is allowed to stand 3.5 hours at 25° C., then is dilutedwith 75 ml. of water and extracted once with ethyl acetate to remove anyneutral material. The aqueous layer is separated, made acid with dilutehydrochloric acid and extracted 4 times with ethyl acetate. The extractsare combined of washed 3 times with water, once with brine, dried oversodium sulfate, and evaporated to givedl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α.

A solution of 251 mg. of dl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.βmethyl ester in a mixture of 7.5 ml. of methanol and 2.5 ml. of water iscooled to 5° C. and 1.0 ml. of 45% aqueous potassium hydroxide is added.The mixture is allowed to stand 2.5 hours at 25° C. and is diluted withwater and extracted with ethyl acetate to remove neutral material. Theaqueous layer is made acid with dilute hydrochloric acid and extractedwith ethyl acetate. The ethyl acetate extracts are washed with water,and brine, dried over sodium sulfate and evaporated to givedl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.β.

Following the procedures of Example 9, the corresponding 4-oxa methyl orethyl esters are transformed todl-4-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β. Likewisethe 3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and -PGF₁.sub.βethyl esters are transformed to the dl-3-oxa (or-4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and -PGF₁.sub.β.

EXAMPLE 10

dl-15-Epi-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α Ethyl Ester anddl-15-Epi-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.β Ethyl Ester(Formula XIX: C_(n) H_(2n) is -(CH₂)₃ -; C_(t) H_(2t) is ethylene; R₁ isethyl; R₂, R₃, R₄, R₅, and R₆ are hydrogen; s is zero; and ˜ is alpha orbeta).

A solution of dl-15-epi-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester(650 mg.), hexamethyl disilazane (5 ml.) and trimethylchlorosilane (1ml.) in 25 ml. of tetrahydrofuran is allowed to stand for 20 hours atabout 25° C. The mixture is concentrated under reduced pressure to givethe 11,15-bis(trimethylsilyl)ether ofdl-15-epi-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester as a viscousoil. This ether is dissolved in 135 ml. of methanol, cooled to -5° C.,and a solution of sodium borohydride (0.5 g.) in 25 ml. of ice-coldmethanol is added. The mixture is allowed to stand 30 minutes at 0° C.,then 10 ml. of acetone is added, and the mixture is made slightly acidicwith acetic acid. This mixture is stirred at about 25° C. for 3 hours,then concentrated under reduced pressure to remove the methanol andacetone. The aqueous residue is extracted with ethyl acetate and theextract is washed with water and brine, dried over sodium sulfate, andevaporated under reduced pressure to give a residue. This residue ischromatographed over 140 g. of silica gel wet-packed in ethyl acetate,eluting with 150 ml. of 3%, 450 ml. of 5%, and 450 ml. of 7.5% ethanolin ethyl acetate, taking 15-ml. fractions. Fractions 29-41 areevaporated to give 344 mg. ofdl-15-epi-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α ethyl ester; massspectral peaks at 420, 402, 384 and 330.

Fractions 54-65 are evaporated to give 86 mg. ofdl-15-epi-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.β ethyl ester.

Also following the procedures of Examples 8 and 10, the methyl ester andfree acid forms of Formula XIX-to-XXVI PGF compounds in their variousspatial configurations, e.g., 8-iso-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β,8-iso-15-epi-3-oxa (or 4-oxa)-17-phenyl-18,19,20-trinor-PGF₁.sub.α and-PGF₁.sub.β, 3-oxa (or 4-oxa)-17-phenyl-18,19,20-trinor-PGF₂.sub.α and-PGF₂.sub.β, 15-epi-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₂.sub.α and -PGF₂.sub.β, 8-iso-3-oxa(or 4-oxa)-17-phenyl-18,19,20-trinor-PGF₂.sub.α and -PGF₂.sub.β,8-iso-15-epi-3-oxa (or 4-oxa)-17-phenyl-18,19,20-trinor-PGF₂.sub.α and-PGF₂.sub.β, trans-5,6-dehydro-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β,trans-5,6-dehydro-15-epi-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β,trans-5,6-dehydro-8-iso-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β,trans-5,6-dehydro-8-iso-15-epi-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β,5,6-dehydro-3-oxa (or 4-oxa)-17-phenyl-18,19,20-trinor-PGF₂.sub.α andPGF₂.sub.β, 5,6-dehydro-15-epi-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₂.sub.α and -PGF₂.sub.β,5,6-dehydro-8-iso-3-oxa (or 4-oxa)-17-phenyl-18,19,20-trinor-PGF₂.sub.αand -PGF₂.sub.β, 5,6-dehydro-8-iso-15-epi-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₂.sub.α and -PGF₂.sub.β,13,14-dihydro-3-oxa (or 4-oxa)-17-phenyl-18,19,20-trinor-PGF₁.sub.α and-PGF₁.sub.β, 13,14-dihydro-15-epi-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β,13,14-dihydro-8-iso-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β,13,14-dihydro-8-iso-15-epi-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β,15-epi-3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and-PGF₁.sub.β, 8-iso-3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and-PGF₁.sub.β, 8-iso-15-epi-3-oxa (or4-oxa)-18-phenyl-19,20-dinor-PGF₂.sub.α and -PGF₂.sub.β,trans-5,6-dehydro-3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and-PGF₁.sub.β, trans-5,6-dehydro-15-epi-3-oxa (or4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and -PGF₁.sub.β,trans-5,6-dehydro-8-iso-3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and -PGF₁.sub.β,trans-5,6-dehydro-8-iso-15-epi-3-oxa (or4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and -PGF₁.sub.β,5,6-dehydro-3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGF₂.sub.α and-PGF₂.sub.β, 5,6-dehydro-15-epi-3-oxa (or4-oxa)-18-phenyl-19,20-dinor-PGF₂.sub.α and -PGF₂.sub.β,5,6-dehydro8-iso-3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGF₂.sub.α and-PGF₂.sub.β, 5,6-dehydro-8 -iso-15-epi-3-oxa (or4-oxa)-18-phenyl-19,20-dinor-PGF₂.sub.α and -PGF₂.sub.β,13,14-dihydro-3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and-PGF₁.sub.β, 13,14-dihydro-15-epi-3-oxa (or4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and -PGF₁.sub.β,13,14-dihydro-8-iso-3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.αand -PGF₁.sub.β, 13,14-dihydro-8-iso-15-epi-3-oxa (or4-oxa)-18-phenyl-19,20-dinor-PGF₁.sub.α and -PGF₁.sub.β, are prepared byreduction of the corresponding 3-oxa or 4-oxa 17-phenyl-18,19,20-trinor-or 18-phenyl-19,20-dinor-PGE type methyl ester or free acid.

Also following the procedure of Examples 8 and 10, each of the other3-oxa or 4-oxa phenyl-substituted PGE-type esters and free acids definedabove in and after Examples 6 and 7, and hereafter in Examples 14 and15, is transformed to the corresponding 3-oxa or 4-oxaphenyl-substituted PGF.sub.α-type and PGF.sub.β-type ester and freeacid.

EXAMPLE 11

dl-15-Dehydro-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α Ethyl Ester(Formula LXXXIII (Chart J): E is trans --CH=CH--; Q is ##SPC58##

R₁ is ethyl; R₂ is hydrogen; V is --(CH₂)₃ --O-CH₂ --; and ˜ is alpha).

A solution of dl-15-epi-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α ethylester (566 mg.) in 24 ml. of dioxane is stirred at 50° C. under nitrogenand 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.37 g.) is added. Themixture is stirred at 50° C. for 24 hours, cooled to room temperature,and filtered. The filter cake is washed with tetrahydrofuran, and thefiltrate and wash are combined and concentrated under reduced pressure.The residue is taken up in dichloromethane and washed with brine, thendried over sodium sulfate and evaporated under reduced pressure. Theresidue is chromatographed over 90 g. of silica gel wet-packed in 8%ethanol in dichloromethane, eluting with 300 ml. of 2%, 300 ml. of 3%,225 ml. of 7.5% and 245 ml. of 10% ethanol in dichloromethane, taking15-ml. fractions. Fractions 65-71 are evaporated to give 413 mg. of thedesired dl-15-dehydro-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α ethylester: NMR peaks at 7.22, 6.95-6.30 (multiplet), 4.35-3.97 (multiplet),3.65-3.45 (triplet), 2.91, 1.66-1.42, and 1.36-1.13 (multiplet) δ.

EXAMPLE 12

dl-15-Methyl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α Ethyl Ester(Formula XIX: C_(n) H_(2n) is --(CH₂)₃ --; C_(t) H_(2t) is ethylene; R₁is ethyl; R₂, R₄, R₅, and R₆ are hydrogen; R₃ is methyl; s is zero; and˜ is alpha).

The steps shown in Chart J are followed. A solution ofdl-15-dehydro-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α ethyl ester(413 mg.), hexamethyldisilazane (3 ml.) and trimethylchlorosilane (0.5ml.) in 20 ml. of tetrahydrofuran is allowed to stand at about 25° C.for 20 hours. The mixture is filtered twice through a bed ofdiatomaceous earth (Celite Filter Aid) and the filtrate is concentratedby evaporation under reduced pressure. Xylene (10 ml.) is added to theresidue and removed by evaporation under reduced pressure. The residueis dissolved in anhydrous ether and 0.43 ml. of 3 M methyl magnesiumbromide in ether is added. The mixture is allowed to stand 20 minutes atabout 25° C. and poured into 100 ml. of saturated aqueous ammoniumchloride. The ether layer is separated, the aqueous layer is extractedwith ether, and the ether extracts are combined and washed with brine,dried over sodium sulfate, and evaporated under reduced pressure. Theresidue is dissolved in 300 ml. of ethanol and 30 ml. of watercontaining 3 drops of glacial acetic acid, and the mixture is stirredfor 2 hours at about 25° C. The mixture is concentrated under reducedpressure to an aqueous residue and the residue is extracted withdichloromethane. The dichloromethane extract is evaporated under reducedpressure to give a residue which is chromatographed over 60 g. of silicagel wet-packed in 8% ethanol in dichloromethane, eluting with 200 ml. of5% and 800 ml. of 10% ethanol in dichloromethane and taking 10-ml.fractions. Fractions 48-62 are evaporated to give 93 mg. of the desireddl-15-methyl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α ethyl ester: NMRpeaks at 7.23, 5.64-5.52 (multiplet), 4.37-4.13 (multiplet), 4.08, 1.5,1.35, 1.38-1.15 (multiplet) δ. Other fractions yield the 15-epicompound.

Following the procedures of Examples 11 and 12, but usingdl-15-epi-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.β ethyl ester insteadof the PGF₁.sub.α compound, there is obtained first the 15-dehydroPGF₁.sub.β compound, and finally the15-methyl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.β ethyl ester, andits 15-epimer.

Likewise, using the corresponding 4-oxa PGF₁.sub.α or PGF₁.sub.βcompounds instead of the 3-oxa compounds, there are obtained thecorresponding 15-dehydro 4-oxa PGF₁.sub.α or PGF₁.sub.β compounds, andfinally the 15-methyl-4-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α or-PGF₁.sub.β ethyl esters and their 15-epimers.

Likewise, using the corresponding 18-phenyl-19,20-dinor-PGF₁.sub.α orPGF₁.sub.β compounds instead of the above17-phenyl-18,19,20-trinor-PGF₁.sub.α or PGF₁.sub.β compounds, there areobtained the corresponding 15-dehydro and 15-methyl18-phenyl-19,20-dinor-PGF₁.sub.α or -PGF₁.sub.β compounds, and their15epimers.

EXAMPLE 13

Ethyl7-[Endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-cis-5-heptenoate(Formula XLV: Q is ##SPC59##

R₂, r₃, and R₄ are hydrogen; R₁₀ is ethyl; V is cis--CH=CH--CH₂ --O-CH₂--; and ˜ is endo and alpha).

The series of steps shown in Chart E is employed. The compoundrepresented by Formula LVIII is prepared prior to forming the ketalXLIII.

A solution of potassium chlorate (10.0 g.) and osmium tetroxide (0.65g.) in 250 ml. of water is added with stirring to a solution of theFormula-L product (approximately 10.0 g.) of Example 1. The mixture isstirred vigorously for 5 hours at 50° C. Then, the cooled mixture isconcentrated under reduced pressure. The residue is extracted repeatedlywith dichloromethane, and the combined extracts are dried andevaporated. The residue is chromatographed on about 1000 g. of silicagel, and eluted successively with 3 l. of 10% ethyl acetate in a mixtureof isomeric hexanes (Skellysolve B), with 5 l. of 25% ethyl acetate inSkellysolve B, and then with 50% ethyl acetate in Skellysolve B,collecting 500 ml. eluate fractions. Fractions 13-19 (50% ethyl acetate)are combined and evaporated to dryness to giveendo-6(1,2-dihydroxy-4-phenylbutyl)-bicyclo[3.1.0]hexan-3-one (FormulaLVIII).

A solution of the Formula-LVIII dihydroxy compound above (about 8.0 g.)and 700 mg. of potassium bisulfate in 140 ml. of acetone is stirred at25° C. for 64 hours. Then, sodium carbonate monohydrate (710 mg.) isadded, and the mixture is stirred 10 minutes. The acetone is evaporatedat reduced pressure, and water is added. The aqueous solution esextracted respectedly with dichloromethane, and the extracts arecombined, washed with water, dried, and evaporated. The residue ischromatographed on 400 g. of silica gel, being eluted with 2 l. of 10%ethyl acetate in Skellysolve B, and then with 4 l. of 15% ethyl acetatein Skellysolve B. The 15% ethyl acetate eluates are evaporated to giveendo-6-(1,2-dihydroxy-4-phenylbutyl)-bicyclo[3.1.0]hexan-3-one acetonide(Formula XLIII).

Following the procedure of Example 3, but using the Formula-XLIIIcompound above instead of theendo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one compound, theFormula-XLIII compound is alkylated with ethyl7-iodo-3-oxacis-5-heptenoate to give ethyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-cis-5-heptenoateacetonide (Formula XLIV).

Concentrated hydrochloric acid (2.5 ml.) is added to a solution of theFormula-XLIV product above (about 2.0 g.) in a mixture of 50 ml. oftetrahydrofuran and 2.5 ml. of water. The mixture is stirred at 25°C.under nitrogen for 6 hours. The resulting mixture is then evaporatedunder reduced pressure, and the residue is extracted with ethyl acetate.The extract is washed with saturated aqueous sodium chloride solution,dried, and evaporated to give ethyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-cis-5-heptenoate(Formula XLV).

Following the procedure of Example 13, but using Formula L exo reactantsin place of the endo reactant from Example 1, there are obtained exoproducts in each intermediate and final step of Example 13.

With excess base (e.g., 26 g.) and a longer reaction time (e.g., 24hours at 25°C.) during the alkylation step, the production of asubstantial amount of the beta isomer is assured.

Following the procedure of Example 13, but using the intermediateFormula-L compound of Example 2, viz.,endo-6-(cis-5-phenyl-1-pentenyl)bicyclo[3.1.0]hexan-3-one, instead ofthe 4-phenyl-1-butenyl compound of Example 1, there is obtained theFormula-XLV product, ethyl7-[endo-6-(1,2-dihydroxy-5-phenylpentyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-cis-5-heptenoate.

Also following the procedure of Example 13 but using the Formula-Lproducts following Example 2 instead of the 4-phenyl-1-butenyl compoundof Example 1, there are obtained other compounds corresponding to theFormula-XLV product of Example 13. For example, the3-fluoro-3-phenyl-1-propenyl Formula-L compound yields ethyl7-[endo-6-(1,2-dihydroxy-3-fluoro-3-phenylpropyl)-3-oxo-bicyclo[3.1.0]hex-2α-yl-3-oxa-cis-5-heptenoate.Depending upon the reactants and the conditions employed, as disclosedhereinabove, there are obtained products in the alpha or beta exo orendo configuration.

Also following the procedure of Example 13 but using in place of ethylcis-7-iodo-3-oxa-cis-5-heptenoate in the alkylation step, ethyl7-iodo-4-oxa-heptanoate, ethyl 3-fluoro-7-iodo-4-oxa-heptanoate, ethyl7-iodo-3-oxa-trans-5-heptenoate, and ethyl 7-iodo-3-oxa-5-heptynoate,there are obtained alpha and beta exo and endo compounds correspondingto the product of Example 13 with --(CH₂)₃ -O-(CH₂)₂ COOEt, --(CH₂)₃--O-CHF--COOEt, trans--CH₂ CH=CH--CH₂ --O--CH₂ -COOEt, and --CH₂C.tbd.C-CH₂ --O-CH₂ COOEt, respectively, wherein Et is ethyl, in placeof the cis --CH₂ CH=CH--CH₂ --O--CH₂ -- moiety of the Example 13product. In the same manner, but using Formula-LX-to-LXVII alkylatingagents within the scope of the formula ##EQU100## there are obtained thecorresponding Formula-XLV products.

In the same manner, but using, according to Example 13, other esters ofthe Example 1 alkylating agent and of the other above-mentionedalkylating agents within the scope of R₁₀ as above-defined, e.g., themethyl, isopropyl, tertbutyl, octyl, β, β,β,-trichloroethyl, cyclohexyl,benzyl, and phenyl esters, there are obtained the corresponding estersof these alpha and beta exo and endo Formula-XLIV bicyclo[3.1.0]hexanecyclic ketal alkylation products.

Also following the procedure of Example 13 but using in combination eachof the above-described alternative Formula-XLIII bicyclo[3.1.0]hexanecyclic ketal reactants and each of the above-described omega-haloalkylation reactants within the scope of ##EQU101## there are obtainedFormula-XLIV compounds corresponding to the product of Example 13 butdifferent therefrom with respect to both the carboxylateterminated sidechain and the side chain attached to the cyclopropane ring of theproduct, and in their respective alpha or beta and exo or endoconfiguration.

Following the procedure of Example 13 but using in place of theacetonide each of the specific Formula-XLIV exo and endo, alpha andbeta, saturated, cis and trans ethylenic, and acetylenicbicyclo[3.1.0]hexane cyclic ketal esters defined above, there areobtained the corresponding Formula-XLV dihydroxy compounds. R₁₀ persistsunchanged during this transformation, e.g., the Formula-XLVβ,β,β,-trichloroethyl dihydroxy ester is obtained from the Formula-XLIVβ,β,β-trichloroethyl cyclic ketal ester.

EXAMPLE 14

3-Oxa or 4-Oxa Phenyl-substituted PGE₁, PGE₂, dehydro PGE₂, and dihydroPGE₁ type Esters.

The steps of Chart E are followed. Thus, following the procedure ofExample 6, each of the Formula-XLV dihydroxy compounds of Example 13 istransformed to the corresponding Formula-XLVI bis-mesyl ester and thenceto the Formula-XLVII PGE type compound. There are thus obtained thespecific PGE type esters represented by Figures XI-XVIII, inclusive,e.g. the esters of 3-oxa (or 4-oxa)-17-phenyl-18,19,20-trinor-PGE₁ ;3-oxa (or 4-oxa)-18-phenyl-19,20-dinor-PGE₁ ; 3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGE₂ ; 3-oxa (or4-oxa)-18-phenyl-19,20-dinor-PGE₂ ; 5,6-dehydro-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGE₂ ; 5,6-dehydro-3-oxa (or4-oxa)-18-phenyl-19,20-dinor-PGE₂ ; 13,14-dihydro-3-oxa (or4-oxa)-17-phenyl-18,19,20-trinor-PGE₁ ; and 13,14-dihydro-3-oxa (or4-oxa)-18-phenyl-19,20-dinor-PGE₁ ; including their cis and trans forms,their 8-iso, and their 15-epi forms.

EXAMPLE 15

13,14-Dihydro-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ (Formula XVII: C_(n)H_(2n) is --(CH₂)₃ --; C_(t) H_(2t) is ethylene; R₁, R₂, R₃, R₄, R₅, andR₆ are hydrogen; s is zero; and ˜ is alpha).

The procedures shown in Charts B and C are followed. A solution of3-oxa-17-phenyl-18,19,20-trinor-PGE₁ (100 mg.) in 10ml. of ethyl acetateis shaken with hydrogen at about one atmosphere pressure at 25°C. in thepresence of 5% palladium on charcoal (15 mg.). One equivalent ofhydrogen is absorbed in about 90 minutes. The hydrogenation is thenstopped, and the catalyst is removed by filtration. The filtrate isevaporated, and the residue is chromatographed on 25 g. of silica gel,eluting with 50-100% ethyl acetate gradient in Skellysolve B. Thosefractions shown by TLC to contain the desired product free of thestarting product and dehydration products are combined and evaporated togive 13,14-dihydro-3-oxa-17-phenyl-18,19,20-trinor-PGE₁.

Following the procedure of Example 15,3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester is reduced to13,14-dihydro-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester.Likewise, 4-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester is reduced to13,14-dihydro-4-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester. Alsofollowing the procedure of Example 15, 3-oxa-18-phenyl-19,20-dinor-PGE₁ethyl ester is reduced to 13,14-dihydro-3-oxa-18-phenyl-19,20-dinor-PGE₁ethyl ester.

Also following the procedure of Example 15,3-oxa-17-phenyl-18,19,20-trinor-PGE₂,trans-5,6-dehydro-3-oxa-17-phenyl-18,19,20-trinor-PGE₁, and5,6-dehydro-3-oxa-17-phenyl-18,19,20-trinor-PGE₂ are each reduced to13,14-dihydro-3-oxa-17-phenyl-18,19,20-trinor-PGE₁, using twoequivalents of hydrogen for the first two reactions, and threeequivalents of hydrogen for the third. Likewise, the corresponding 4-oxacompounds are reduced to13,14-dihydro-4-oxa-17-phenyl-18,19,20-trinor-PGE₁.

Also following the procedure of Example 15, the ethyl ester and the freeacid form of the Formula XI-to-XVI PGE compounds in their variousspatial configurations are transformed to the corresponding13,14-dihydro PGE₁ compound by catalytic hydrogenation, usingequivalents of hydrogen appropriate to the degree of unsaturation of thereactant, i.e., one equivalent for the PGE₁ type, two equivalents forthe PGE₂ type and trans-5,6-dehydro-PGE₁ type, and three equivalents forthe 5,6-dehydro-PGE₂ type.

Also following the procedure of Example 15,3-oxa-phenyl-18,19,20-trinor-PGF₁.sub.α and its ethyl ester are reducedto 13,14-dihydro-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α and itsethyl ester, respectively.

Also following the procedure of Example 15, the ethyl ester and the freeacid form of the Formula XIX-to-XXIV PGF compounds in their variousspatial configurations are transformed to the corresponding13,14-dihydro PGF₁.sub.α or PGF₁.sub.β compound by catalytichydrogenation, using equivalents of hydrogen appropriate to the degreeof unsaturation of the reactant.

EXAMPLE 16

13,14-Dihydro-3-oxa-17-phenyl-18,19,20-trinor-PGA₁ (Formula XXXIII:C_(n) H_(2n) is --(CH₂)₃ --; C_(t) H_(2t) is ethylene; R₁, R₂, R₃, R₄,R₅, and R₆ are hydrogen; s is zero; and ˜ is alpha).

The procedures shown in Charts B and C are followed. A suspension ofdisodium azodiformate (50 mg.) in 5 ml. of absolute ethanol is added toa stirred solution of 3-oxa-17-phenyl-18,19,20-trinor-PGA₁ (50 mg.) in10 ml. of absolute ethanol under nitrogen at 25°C. The mixture is madeacid with glacial acetic acid, and then is stirred under nitrogen at25°C. for 8 hours. The resulting mixture is evaporated under reducedpressure, and the residue is mixed with a mixture of diethyl ether andwater (1:1). The diethyl ether layer is separated, dried, and evaporatedto give the product 13,14-dihydro-3-oxa-17-phenyl-18,19,20-trinor-PGA₁.

Following the procedure of Example 16,3-oxa-17-phenyl-18,19,20-trinor-PGA₁ methyl ester is reduced to13,14-dihydro-3-oxa-17-phenyl-18,19,20-trinor-PGA₁ methyl ester.

Also following the procedure of Example 16,3-oxa-17-phenyl-18,19,20-trinor-PGA₂,trans-5,6-dehydro-3-oxa-17-phenyl-18,19,20-trinor-PGA₁, and5,6-dehydro-3-oxa-17-phenyl-18,19,20-trinor-PGA₂ are each reduced to13,14-dihydro-3-oxa-17-phenyl-18,19,20-trinor-PGA₁, using amounts of thedisodium azodiformate reactant appropriate to the degree of unsaturationof the reactant.

Also following the procedure of Example 16, the methyl ester and thefree acid form of the Formula XI-to-XVI PGE type compounds, the FormulaXIX-to-XXIV PGF type compounds, the Formula XXVII-to-XXXII PGA typecompounds, and the Formula XXXV-to-LX PGB type compounds are transformedto the corresponding 13,14-dihydro PGE₁, PGF₁, PGA₁, or PGB₁ typecompound by diimide reduction, using amounts of disodium azodiformatereactant appropriate to the degree of unsaturation of the PGE, PGF, PGA,or PGB type reactant.

EXAMPLE 17

dl-4-Oxa-17-phenyl-18,19,20-trinor-PGF₂.sub.α Methyl Ester (FormulaXXII: C_(q) H_(2q) is methylene; C_(t) H_(2t) is ethylene; R₁ is methyl;R₂, R₃, R₄, R₅ , R₆, R₇, and R₈ are hydrogen; s is zero; and ˜ is alpha.

The transformation shown in Chart D is used.dl-5,6-Dehydro-4-oxa-17-phenyl-18,19,20-trinor-PGF₂.sub.α methyl ester(200 mg.) in pyridine (4 ml.) and methanol (10 ml.) is hydrogenated inthe presence of a 5%-palladium-on-barium sulfate catalyst (200 mg.) at25° and atmospheric pressure. The reaction is terminated when oneequivalent of hydrogen is absorbed. The mixture is filtered andevaporated. Ethyl acetate is added and residual pyridine is removed byaddition of ice and 3 N. hydrochloric acid. The ethyl acetate layer iswashed with 1 N. hydrochloric acid and then with saturated aqueoussodium chloride solution, dried, and evaporated to yielddl-4-oxa-17-phenyl-18,l9,20-trinor-PGF₂.sub.α methyl ester.

Following the procedure of Example 17, the specific 5,6-dehydro-3-oxa(or 4-oxa) phenyl-substituted compounds following Example 10 are reducedto the corresponding PGF₂ compounds. Likewise, the specific5,6-dehydro-3-oxa (or 4-oxa) phenyl-substituted PGE, PGA, and PGBcompounds herein are reduced to the corresponding PGE₂, PGA₂, and PGB₂compounds.

EXAMPLE 18

3-Oxa-17-phenyl-18,19,20-trinor-PGA₁ Ethyl Ester and Free Acid (FormulaXXVII: C_(n) H_(2n) is --(CH₂)₃ --; C_(t) H_(2t) is ethylene; R₁ isethyl or hydrogen; R₂, R₃, R₄, R₅, and R₆ are hydrogen; s is zero; and ˜is alpha).

The procedures shown in Chart A are followed.

I. Using hydrochloric acid. A solution of3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester (400 mg.) in a mixtureof tetrahydrofuran (5 ml.) and 0.5 N hydrochloric acid (5 ml.) ismaintained under nitrogen at 25° C. for 5 days. The resulting mixture isdiluted with one volume of saturated aqueous sodium chloride solutionand extracted with a mixture of diethyl ether and dichloromethane (3:1).The extract is washed with saturated aqueous sodium chloride solution,dried, and evaporated. The residue is dissolved in diethyl ether, andthe solution is extracted with cold 5% aqueous sodium bicarbonatesolution to give an aqueous layer A and a diethyl ether layer B. Aqueouslayer A is acidified with dilute hydrochloric acid and then extractedwith dichloromethane. This extract is washed with saturated aqueoussodium chloride solution, dried, and evaporated to give the product freeacid. Diethyl ether layer B is evaporated to give the product ethylester.

II. Using acetic acid. A solution of3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester in a mixture of aglacial acetic acid (9 ml.) and water (1 ml.) is heated under nitrogenat 60° C. for 18 hours. Then, the acetic acid and water are evaporatedunder reduced pressure, and the residue is chromatographed on 50 g. ofacid-washed silica gel, eluting with a 25-100% gradient of ethyl acetatein Skellysolve B. The fractions containing the desired product free ofstarting material as shown by TLC are combined and evaporated to givethe product, 3-oxa-17-phenyl-18,19,20-trinor-PGA₁ ethyl ester.

Following the procedure of Example 18, the4-oxa-17-phenyl-18,19,20-trinor-PGE₁ free acid is transformed to4-oxa-17-phenyl-18,19,20-trinor-PGA₁ free acid.

Also following the procedure of Example 18, the Formula XI-to-XVIII PGEcompounds in their various spatial configurations are transformed to thecorresponding Formula XXVII-to-XXXIV PGA compounds, either as esters oras free acids.

EXAMPLE 19

3-Oxa-17-Phenyl-18,19,20-trinor-PGA₁ Methyl Ester (Formula XXVII: C_(n)H_(2n) is --(CH₂)₃ --; C_(t) H_(2t) is ethylene; R₁ is methyl; R₂, R₃,R₄, R₅, and R₆ are hydrogen; s is zero; and ˜ is alpha).

The procedure shown in Chart E to prepare the compounds of FormulaXLVIII is used. A solution of methyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxobicyclo[3.1.0.]hex-2α-yl]-3-oxaheptanoate bis(methanesulfonate) of Example 6 (Formula XLVI) (about 10g.) in 75 ml. of acetone is mixed with 10 ml. of water and 20 ml. ofsaturated aqueous sodium bicarbonate solution. The mixture is refluxedunder nitrogen for 4 hours. Then, the mixture is cooled, acidified with5% hydrochloric acid, and extracted with ethyl acetate. The extract iswashed with saturated aqueous sodium chloride solution, dried, andevaporated to give 3-oxa-17-phenyl-18,19,20-trinor-PGA₁ methyl ester.

Following the procedure of Example 19, each of the bismesylates definedin Example 14 is transformed to the corresponding PGA-type ester,including the β,β,β-trichloroethyl esters. Thereafter, each of theβ,β,β-trichloroethyl esters is transformed to the corresponding PGA-typefree acid by the procedure of Example 7.

EXAMPLE 20

3-Oxa-17-phenyl-18,19,20-trinor-PGB₁ (Formula XXXV: C_(n) H_(2n) is--(CH₂)₃ --; C_(t) H_(2t) is ethylene; R₁, R₂, R₃, R₄, R₅, and R₆ arehydrogen; and s is zero).

The procedure shown in Chart A is followed. A solution of3-oxa-17-phenyl-18,19,20-trinor-PGE₁ (200 mg.) in 100 ml. of 50% aqueousethanol containing 10 grams of potassium hydroxide is kept at 25° C. for10 hours under nitrogen. Then, the solution is cooled to 10° C. andneutralized by addition of 3 normal hydrochloric acid at 10° C. Theresulting solution is extracted repeatedly with ethyl acetate, and thecombined ethyl acetate extracts are washed with water and then withsaturated aqueous sodium chloride solution, dried, and evaporated togive 3-oxa-17-phenyl-18,19,20-trinor-PGB₁.

Following the procedure of Example 20,3-oxa-17-phenyl-18,19,20,-trinor-PGA₁ is transformed to 3-oxa-17-phenyl-18,19,20-trinor-PGB₁.

Following the procedure of Example 20, the Formula XI- to-XVIII PGEcompounds and the Formula XXVII-to-XXXIV PGA compounds are transformedto the corresponding PGB compounds.

EXAMPLE 21

7-[Endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-5-heptenoicacid acetonide (Formula LXXII: Q is ##SPC60##

R₂, r₃, and R₄ are hydrogen; R₁₁ and R₁₂ are methyl; V is --CH=CH--CH₂--O--CH₂ --; and ˜ is endo and alpha).

The steps of this preparation are shown in Chart G. A solution of sodiumborohydride (1.5 g.) in 10 ml. of water is added with stirring to asolution of Formula-LXVIII ethyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxobicyclo[3.1.0]-hex-2α-yl]-3-oxa-5-heptenoateacetonide (5.0 g.) in 110 ml. of absolute ethanol at 0° C. The mixtureis stirred for 2.5 hours at 0° to 5° C. Then, 40 ml. of acetone isadded, and, after 5 minutes, the mixture is evaporated under reducedpressure. The residue is extracted with dichloromethane, and the extractis washed successively with dilute hydrochloric acid and saturatedaqueous sodium chloride solution, dried, and evaporated to give theFormula-LXIX compound, ethyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-hydroxy-bicyclo[3.1.0]hex-2α-yl]-3-oxa-5-heptenoate acetonide.

This cyclic ketal hydroxy ester is dissolved in a mixture of methanol(100 ml.) and 45% aqueous potassium hydroxide solution (30 ml.), and thesolution is stirred under nitrogen at 25° C. for 15 hours. Two volumesof water are then added, and the mixture is acidified with coldhydrochloric acid and then extracted with a mixture of dichloromethaneand diethyl ether (1:3). The extract is washed with saturated aqueoussodium chloride solution, dried, and evaporated to give the Formula-LXXcompound,7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-hydroxybicyclo[3.1.0]hex-2.alpha.-yl]-3-oxa-5-heptenoicacid acetonide.

Jones reagent (7 ml.; Preparation 4) is added to a solution of thishydroxy acid in 120 ml. of acetone at 0° C. The mixture is stirred 5minutes at 0° C. Then, 5 volumes of water are added, and the mixture isextracted with a mixture of dichloromethane and diethyl ether (1:3). Theextract is washed successively with dilute hydrochloric acid andsaturated aqueous sodium chloride solution, dried, and evaporated togive the Formula-LXXII compound,7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxo-bicyclo[3.1.0]hex-2α-yl]-3-oxa-5-heptenoicacid acetonide.

Following the procedure of Example 21 but substituting for theFormula-LXVIII 3-oxobicyclo[3.1.0]hexane ester acetonide, each of thespecific endo and exo, alpha and beta, saturated, cis and transethylenic, and acetylenic ester cyclic ketals described in and afterExample 13 is reduced with sodium borohydride to give the correspondingFormula-LXIX 3-hydroxybicyclo[3.1.0]hexane ester cyclic ketal. Thathydroxy ester is then saponified as in Example 21 to the correspondingFormula-LXX hydroxy acid. That hydroxy acid is then oxidized as inExample 21 to the corresponding Formula-LXXII 3-oxobicyclo[3.1.0]hexaneacid cyclic ketal.

EXAMPLE 22

7-[Endo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-4-oxaheptanoicacid (Formula LXXVIII: Q is ##SPC61##

R₂, r₃, and R₄ are hydrogen; Z is --(CH₂)₂ --O--(CH₂)₂ -; and ˜ is endo,and alpha).

The steps of this preparation are shown in Chart H. Following theprocedure of Example 21, the Formula-LXXIV compound, methyl7[endo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-4-oxaheptanoate is reduced with sodium borohydride to the Formula-LXXVcompound, methyl7-[endo-6-(cis-4-phenyl-1-butenyl)-3-hydroxybicyclo[3.1.0]-hex-2α-yl]-4-oxaheptanoate.That hydroxy ester is then saponified as described in Example 21 to theFormula-LXXVI compound,7-[endo-6-(cis-4-phenyl-1-butenyl)-3-hydroxybicyclo[3.1.0]hex-2α-yl]-4-oxaheptanoic acid. That hydroxy acid is then oxidized as described inExample 21 to the Formula-LXXVIII product,7-[endo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-4-oxaheptanoic acid.

Following the procedure of Example 22, but using in place of theFormula-LXXIV 3-oxobicyclo[3.1.0]hexane ester, each of the specificFormula-LXXIV endo and exo, alpha and beta, saturated and acetylenicesters described in and following Examples 3 and 4 is reduced withsodium borohydride to give the corresponding Formula-LXXV3-hydroxybicyclo[3.1.0] hexane ester. That hydroxy ester is thensaponified as described in Example 21 to the corresponding Formula-LXXVI3-hydroxybicyclo[3.1.0]hexane acid. That hydroxy acid is then oxidizedas described in Example 21 to the corresponding Formula-LXXVIII3-oxobicyclo[3.1.0]hexane acid.

EXAMPLE 23

β,β,β-Trichloroethyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-hyroxybicyclo[3.1.0]hex-2α-yl]-3-oxa-5-heptenoateacetonide (Formula LXXI: Q is ##SPC62##

R₂, r₃, and R₄ are hydrogen; R₁₁ and R₁₂ are methyl; haloethyl is β,β,β-trichloroethyl; V is --CH=CH--CH₂ --O-CH₂ --; and ˜ is endo, andalpha).

Successively, β,β,β-trichloroethanol (25 ml.), pyridine (15 ml.), anddicyclohexylcarbodiimide (4.0 g.) are added to a solution of Formula-LXXcompound7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-hydroxybicyclo[3.1.0]hex-2.alpha.-yl]-3-oxa-5-heptenoicacid acetonide (2.0 g.) in 100 ml. of dichloromethane. This mixture isstirred 3 hours under nitrogen at 25° C. Water (50 ml.) is then added,and the mixture is stirred 10 minutes. The dichloromethane is evaporatedunder reduced pressure, and the residue is extracted repeatedly withethyl acetate. The combined extracts are washed with ice-cold 3Nhydrochloric acid. Then, the extracts are washed successively withaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution, dried, and evaporated under reduced pressure. Theresidue is chromatographed on 600 g. of silica gel, eluting with 10 l.of a 20-100% ethyl acetate-Skellysolve B gradient, collecting 250-ml.fraction. The middle fractions which show the presence of a product onTLC (thin-layer chromatography) with the A-IX system are combined andevaporated under reduced pressure. The residue is chromatographed on 200g. of silica gel impregnated with silver nitrate, eluting with 4 l. of a20-100% ethyl acetate-Skellysolve B gradient, collecting 50-ml.fractions. The middle fractions which show a product free of startingmaterials on TLC with the A-IX system are combined and evaporated underreduced pressure to give the product, β,β,β-trichloroethyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-hydroxybicyclo[3.1.0]hex-2.alpha.-yl]-3-oxa-5-heptenoateacetonide.

Following the procedure of Example 23, but using in place of theFormula-LXX 3-hydroxybicylo[3.1.0]hexane acid acetonide, each of thespecific endo and exo, alpha and beta, saturated and unsaturatedFormula-LXX hdyroxy acid ketals defined after Example 21, there areobtained the corresponding β,β,β-trichloroethyl esters of those3-hydroxybicyclo[3.1.0]hexane acids.

Following the procedure of Example 23, but using in place of theFormula-LXX 3-hydroxybicyclo[3.1.0]hexane acid ketal, each of thespecific Formula-LXXII 3-oxo-acid ketals defined after Example 21, thereare obtained the corresponding Formula-LXXIII β,β,β-trichloroethylesters of those 3-oxo-acid ketals.

Following the procedure of Example 23 but using in place of theFormula-LXX 3-hydroxy-acid ketal, each of specific Formula-LXXVI3-hydroxy and Formula-LXXVIII 3-oxo acids defined after Example 22,there are obtained the corresponding Formula-LXXVII and Formula-LXXIXβ,β,β-trichloroethyl esters of those acids, respectively.

Following the procedures of Examples 13 and 14, each of theFormula-LXXIII cyclic ketal haloethyl esters of Example 23 istransformed to the corresponding Formula-XLVII 3-oxa or 4-oxaphenyl-substituted PGE₂ β,β,β-trichloroethyl ester. Thence, followingthe procedure of Example 7, each of the esters is transformed to the3-oxa or 4-oxa phenylsubstituted PGE₂ acid compound wherein R₁₀ ofFormula XLVII is replaced with hydrogen.

Following the procedure of Examples 5 and 6 each of the Formula-LXXIXolefin haloethyl esters of Example 22 is transformed to thecorresponding Formula-XLVII 3-oxa or 4-oxa phenyl-substituted PGE₁β,β,β-trichloroethyl ester. Thence, following the procedure of Example7, each of the esters is transformed to the 3-oxa or 4-oxaphenyl-substituted PGE₁ acid compound wherein R₁₀ of Formula XXXIII isreplaced with hydrogen.

EXAMPLE 24

dl-15-Methyl-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ Methyl Ester (FormulaXI: C_(n) H_(2n) is --(CH₂)₃ --; C_(t) H_(2t) is ethylene; R₁ and R₃ aremethyl; R₂, R₄, R₅, and R₆ are hydrogen; s is zero; and ˜ is alpha.

The process depicted in Chart 1 is used.

A solution of 15-methyl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.αmethyl ester (95 mg.) in 40 ml. of acetone is cooled to -10° C. To it isadded Jones reagent (0.1 ml. of a solution of 21 g. of chromicanhydride, 60 ml. of water, and 17 ml. of concentrated sulfuric acid),precooled to 0° C., with vigorous stirring. After 5 minutes at -10° C.,thin layer chromatography on silica gel (acetic acid:methanol:chloroform; 5:5:90) of a small portion of the reaction mixture indicatesabout 50% reaction completion. An additional 0.06 ml. of Jones reagentis added to the still cold reaction mixture with stirring, and themixture is stirred an additional 5 minutes at -10° C. Isopropyl alcohol(1 ml.) is added to the cold reaction mixture. After 5 minutes, themixture is filtered through a layer of diatomaceous earth (Celite). Thefiltrate is concentrated at reduced pressure, and the residue is mixedwith 5 ml. of saturated aqueous sodium chloride solution. The mixture isextracted repeatedly with ethyl acetate, and the combined extracts arewashed with saturated aqueous sodium chloride solution, dried withanhydrous sodium sulfate, and concentrated at reduced pressure. Theresidue is chromatographed on 20 g. of neutral silica gel, eluting with50% ethyl acetate in Skellysolve B. Evaporation of the eluates gives theproduct, dl-15-methyl-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ methyl ester.

Following the procedure of Example 24, there is substituted for the15-methyl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α methyl ester, thefree acid, the propyl ester, the octyl ester, the cyclopentyl ester, thebenzyl ester, the phenyl ester, the 2,4-dichlorophenyl ester, the2-tolyl ester, or the β,β,β-trichloroethyl ester, there is obtained thecorresponding dl-15-methyl-3-oxa-17-phenyl-18, 19,20-trinor-PGE₁compound.

Following the procedure of Example 24, but substituting for the15-methyl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α methyl ester, themethyl ester of each of the15-methyl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.β, -PGF₂.sub.α,-PGF₂.sub.β, -5,6-dehydro-PGF₂.sub.α, -5,6-dehydro-PGF₂.sub.β,-dihydro-PGF₁.sub.α, and -dihydro-PGF₁.sub.β compounds in their variousR or S configurations and optical isomers is transformed to thecorresponding PGE type compound.

Following the procedure of Example 24, and each of the various15-alkyl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α methyl estercompounds, including the 15-ethyl, 15-propyl, 15-butyl, and15-substituted isomeric forms of propyl and butyl, is transformed to thecorresponding PGE type compound.

Also following the procedure of Example 24, each of the 15-alkylPGF-type acids and esters within the scope of Formula LXXX (Chart I) istransformed to a 15-alkyl PGE-type acid or ester encompassed by FormulaLXXXI.

EXAMPLE 25

15-Methyl-4-oxa-18-phenyl-19,20-dinor-PGA₁ Methyl Ester (Formula XXVII:C_(n) H_(2n) is ethylene; C_(t) H_(2t) is --(CH₂)₃ --; R₁ and R₃ aremethyl; R₂, R₄, R₅, and R₆ are hydrogen; s is zero; and ˜ is alpha).

The process depicted in Chart K is used.

A mixture of 15-methyl-4-oxa-18-phenyl-19,20-dinor-PGE₁ methyl ester (6mg.), dicyclohexylcarbodiimide (20 mg.), copper(II) chloride dihydrate(2 mg.), and diethyl ether (2 ml.) is stirred under nitrogen at 25° C.for 16 hours. Then, additional dicyclohexylcarbodiimide (20 mg.) isadded, and the mixture is stirred an additional 32 hours at 25° C. undernitrogen. The resulting mixture is filtered, and the filtrate isevaporated under reduced pressure. The residue is chromatographed bypreparative thin layer chromatography with the A-IX system to give15-methyl-4-oxa-18-phenyl-19,20-dinor-PGA₁ methyl ester.

Following the procedure of Example 25, but substituting for the 4-oxaphenyl-substituted PGE₁ compound, the methyl esters of15-methyl-4-oxa-17-phenyl-18,19,20-trinor-PGE₂, -5,6-dehydro-PGE₂, and-dihydro-PGE₁, there are obtained the corresponding Formula-LXXXVIIIcompounds, viz., the methyl esters of15-methyl-4-oxa-17-phenyl-18,19,20-trinor-PGA₂, -5,6-dehydro-PGA₂, and-dihydro-PGA₁.

Also following the procedure of Example 25, but substituting for thephenyl-substituted PGE₁ compound, the methyl esters of15-methyl-3-oxa-18-phenyl-19,20-dinor-PGE₁, -PGE₂, -5,6-dehydro-PGE₂,and -dihydro-PGE₁, there are obtained the corresponding Formula-LXXXVIIcompounds, viz., the methyl esters of15-methyl-3-oxa-18-phenyl-19,20-dinor-PGA₁, -PGA₂, -5,6-dehydro-PGA₂,and -dihydro-PGA₁.

Also following the procedure of Example 25, each of the Formula-LXXXVII(Chart K) compounds defined above in Example 24 is transformed to thecorresponding Formula-LXXXVIII compound.

EXAMPLE 26

Enzymatic Hydrolysis of 3-oxa-17-phenyl- 18,19,20-trinor-PGE₁ MethylEster.

A. Enzyme preparation

A medium is prepared consisting of 2% corn steep liquor (a mixture ofequal parts of cerelose and glucose in tap water. This is brought to pH4.5 by adding hydrochloric acid, and 1% of methyl oleate is added. For500 ml. flasks each containing 100 ml. of the above medium areinoculated with Cladosporium resinae (C1-11, ATCC 11,274; and are placedon a shaker at room temperature (about 28° C.) for 4 days. The cultureis then placed in 40 ml. centrifuge tubes and centrifuged at about 2,000rmp. in a clinical centrifuge. The liquid is decanted from thecentrifuge tubes and the collected cells are washed with cold water. Thewashed cells from 2 centrifuge tubes are suspended in 50 ml. of ice cold0.05 M pH 7.0 phosphate buffer and placed in small Waring blender cupchilled with ice. Glass beads are added and the suspended cells arechurned in the blender for 15 minutes. The resulting suspension ofbroken cells is centrifuged in a clinical centrifuged at about 2,000r.p.m. for 15 minutes at room temperature, then the supernatant liquidis collected. This supernatant liquid contains Cladosporium resinaeacylase and is used directly for the hydrolysis of alkyl esters or isstored, preferably frozen, until needed.

B. Esterase hydrolysis

Ten milliliters of the supernatant liquid containing Cladosporiumresinae acylase, prepared as described in part A of this example and 50mg. of 3-oxa-17-phenyl-18,19,20-trinor-PGE₁ methyl ester are shaken atroom temperature under nitrogen for about 19 hours., then 70 ml. ofacetone is added and the mixture is filtered giving a filtrate and aninsoluble residue. The filtrate is evaporated under reduced pressure toa residue comprising 3-oxa-17-phenyl- 18,19,20-trinor-PGE₁. This residueis chromatographed over 10 g. of acid-washed silica gel (Silicar CC-4,Mallinckrodt). Elution is with mixed hexanes (Skellysolve B) containingincreasing amounts of ethyl acetate, collecting 50 ml. fractions. Thosefractions containing 3-oxa-17-phenyl-18,19,20-trinor-PGE₁ are combinedand evaporated to yield the product.

Following the procedure of Example 26, each of the specific methyl,ethyl, and other alkyl esters defined above in and after Examples 6, 14,and 15 is hydrolyzed enzymatically to the corresponding 3-oxa or 4-oxaphenyl-substituted PGE-type free acid.

EXAMPLE 27

4-Oxa-17-phenyl-18,19,20-trinor-PGB₁ Methyl Ester (Formula XXXVI: C_(m)H_(2m) and C_(t) H_(2t) are ethylene; R₁ is methyl; R₂, R₃, R₄, R₅, R₆,R₇, and R₈ are hydrogen; and s is zero).

A solution of diazomethane (about 0.5 g.) in diethyl ether (25 ml.) isadded to a solution of 4-oxa-17-phenyl-18,19,20-trinor-PGB₁ (50 mg.) in25 ml. of a mixture of methanol and diethyl ether (1:1). The mixture isallowed to stand at 25° C. for 5 minutes. Then, the mixture isevaporated to give 4-oxa-17-phenyl-18,19,20-trinor-PGB₁ methyl ester.

Following the procedure of Example 27, each of the other specificphenyl-substituted PGB type, PGA type, PGE type, and PGF type free acidsdefined above is converted to the corresponding methyl ester.

Also following the procedure of Example 27, but using in place of thediazomethane, diazoethane, diazobutane, 1-diazo-2-ethylhexane, anddiazocyclohexane, there are obtained the corresponding ethyl, butyl,2-ethylhexyl, and cyclohexyl esters of4-oxa-17-phenyl-18,19,20-trinor-PGB₁. In the same manner, each of theother specific phenyl-substituted PGB type, PGA type, PGE type, and PGFtype free acids defined above is converted to the corresponding ethyl,butyl, 2-ethylhexyl, and cyclohexyl esters.

EXAMPLE 28

3-Oxa-17-phenyl-18,19,20-trinor-PGE₁ Methyl Ester Diacetate.

Acetic anhydride (5 ml.) and pyridine (5 ml.) are mixed with3-oxa-17-phenyl-18,19,20-trinor-PGE₁ methyl ester (20 mg.), and themixture is allowed to stand at 25° C. for 18 hours. The mixture is thencooled to 0° C., diluted with 50 ml. of water, and acidified with 5%hydrochloric acid to pH 1. That mixture is extracted with ethyl acetate.The extract is washed successively with 5% hydrochloric acid, 5% aqueoussodium bicarbonate solution, water, and saturated aqueous sodiumchloride solution, dried and evaporated to give3-oxa-17-phenyl-18,19,20-trinor-PGE₁ methyl ester diacetate.

Following the procedure of Example 28 but replacing the acetic anhydridewith propionic anhydride, isobutyric anhydride, and hexanoic acidanhydride, there are obtained the corresponding dipropionate,diisobutyrate and dihexanoate derivatives of3-oxa-17-phenyl-18,19,20-trinor-PGE₁ methyl ester.

Also following the procedure of Example 28, but replacing the3-oxa-17-phenyl-18,19,20-trinor-PGE₁ compound with3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β, and15-methyl-3-oxa-17-phenyl-18,19,20-trinor-PGF₁.sub.α and -PGF₁.sub.β,there are obtained the corresponding triacetate derivatives of the3-oxa-17-phenyl-18,19,20-trinor-PGF compounds.

Also following the procedure of Example 28, each of thephenyl-substituted PGE type, PGF type, PGA type, and PGB type esters andfree acids defined above is transformed to the corresponding acetates,propionates, isobutyrates, and hexanoates, the PGE type derivativesbeing dicarboxyacylates, the PGF type derivatives beingtricarboxyacylates, and the PGA type and PGB type derivatives beingmonocarboxyacylates.

EXAMPLE 29

3-Oxa-17-phenyl-18,19,20-trinor-PGE₁ Sodium Salt.

A solution of 3-oxa-17-phenyl-18,19,20-trinor-PGE₁ (100 mg.) in 50 ml.of a water-ethanol mixture (1:1) is cooled to 5° C. and neutralized withan equivalent amount of 0.1 N aqueous sodium hydroxide solution. Theneutral solution is evaporated to give3-oxa-17-phenyl-18,19,20-trinor-PGE₁ sodium salt.

Following the procedure of Example 29 but using potassium hydroxide,calcium hydroxide, tetramethylammonium hydroxide, andbenzyltrimethylammonium hydroxide in place of sodium hydroxide, thereare obtained the corresponding salts of3-oxa-17-phenyl-18,19,20-trinor-PGE₁.

Also following the procedure of Example 29 each of thephenyl-substituted PGE type, PGF type, PGA type, and PGB type acidsdefined above is transformed to the sodium, potassium, calcium,tetramethylammonium, and benzyltrimethylammonium salts.

The various Preparations and Examples given above describe thepreparation of racemic intermediates and final products. Each of theintermediates and final products named and defined above is alsoobtained in each of the enantiomeric forms, d and l, by resolution ofthat compound or by resolution of an intermediate used to prepare thatcompound. For example, d-3-oxa-17-phenyl-18,19,20-trinor-PGA₁ free acidis prepared by resolution of dl-3-oxa-17-phenyl-18,19,-20-trinor-PGA₁free acid (Example 18) or by dehydration as in Example 18 of opticallyactive 3-oxa-17-phenyl-18,19,20-trinor-PGE₁ free acid with the sameabsolute configuration. These resolutions are carried out by proceduresknown in the art, and may be used to obtain prostaglandin-like materialshaving the spatial configuration of the natural prostaglandins, astypified by the following Example.

EXAMPLE 30

Natural Configuration 3-Oxa-17-phenyl-18,19,20-trinor-PGE₂ and-PGF₂.sub.α Methyl Esters (Formula XIII and XXI: C_(n) H_(2n) is--(CH₂)₃ --; C_(t) H_(2t) is ethylene; R₁ is methyl; R₂, R₃, R₄, R₅, andR₆ are hydrogen; s is zero; and ˜ is alpha).

The process shown in Chart E is used to prepare the PGE₂ -type compoundfirst. The Formula-XLIV cyclic ketal intermediate wherein Q is ##SPC63##

R₂, r₃, and R₄ are hydrogen; R₁₀, R₁₁, and R₁₂ are methyl; V is--CH=CH--CH₂ --O--CH₂ --; and ˜ is endo and alpha is prepared followingthe procedures of Example 13.

The formula-XLIV compound is resolved as its optical isomers by themethod of Corey et al., J. Am. Chem. Soc. 84, 2938 (1962), by reactingthis keto compound with optically active L(+)-2,3-butanedithiol in thepresence of p-toluenesulfonic acid. The diastereomeric ketals arecompletely resolved on a preparative chromatographic column, and arethen hydrolyzed separately, following the procedure of Example 13, tothe Formula-XLV dihydroxy componds. Transformation to the Formula-XLVIIPGE₂ -type compounds is accomplished by the procedures of Examples 13and 14. Of the separate diastereoisomers, one corresponds to theconfiguration of natural PGE₂ and the other to its enantiomer.Conversion of the PGE₂ -type compound having the configuration of thenatural product to the PGF₂.sub.α -type methyl ester is done byborohydride reduction following the procedure of Example 8. Thenatural-configuration-PGF₂.sub.α -type free acid is formed from themethyl ester by saponification, following the procedure of Example 9.

EXAMPLE 31

dl-16,16-Dimethyl-3-oxa-17-phenyl-18,19,20-trinor-PGE₂ Ethyl Ester(Formula XIII: C_(p) H_(2p) is methylene; C_(t) H_(2t) is --C(CH₃)₂--CH₂ --; R₁ is ethyl; R₂, R₃, R₄, R₅, and R₆ are hydrogen; s is zero;and ˜ is alpha). Refer to Chart E.

A. (2,2-Dimethyl-3-phenylpropyl) triphenylphosphonium bromide. a.(3-Bromo-2,2-dimethylpropyl)benzene. Following the procedure ofPreparation 7 but replacing 4-phenyl-1-butanol with the equivalentamount of 2,2-dimethyl-3-phenyl-1-propanol, there is obtained(3-bromo-2,2-dimethylpropyl)-benzene.

b. (2,2-Dimethyl-3-phenylpropyl)triphosphonium bromide. Following theprocedure of Preparation 5 but replacing (3-bromopropyl)benzene with theequivalent amount of (3-bromo-2,2-dimethylpropyl)benzene, there isobtained the corresponding phosphonium compound.

B.Endo-6-(cis-3,3-dimethyl-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one(Formula L).- Following the procedure of Example 1 but replacing thatphosphonium halide with the above product of Example 31A, there isobtained the corresponding bicyclo olefin L.

C.Endo-6-(1,2-dihydroxy-3,3-dimethyl-4-phenylbutyl)-bicyclo[3.1.0]hexan-3-oneacetonide (Formula XLIII).- Following the procedures of Example 13, theabove Formula-L compound is transformed first toendo-6-(1,2-dihydroxy-3,3-dimethyl-4-phenylbutyl)-bicyclo[3.1.0]hexan-3-one(Formula LVIII) and thence to the corresponding bicyclo acetonide XLIII.

D. Ethyl7-[endo-6-(1,2-dihydroxy13,3-dimethyl-4-phenylbutyl)-3-oxabicyclo[3.1.0]hex-2α-yl]-3-oxa-cis-5-heptenoateacetonide (Formula XLIV).- Following the procedure of Example 3, butusing the Formula-XLIII compound above instead of theendo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one compound, theFormula XLIII compound is alkylated with ethyl7-iodo-3-oxa-cis-5-heptenoate to give the corresponding Formula-XLIVintermediate.

E. Title compound (Formula XIII (XLVII).- Following the procedure ofExample 13, the above Formula-XLIV compound is hydrolyzed withhydrochloric acid, water, and tetrahydrofuran to the correspondingglycol XLV.

Following the procedure of Example 6, but using the above Formula-XLVglycol instead of the ethyl7-[endo-6-(1,2-dihydroxy-4-phenylbutyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxaheptanoate,and finally subjecting the reaction product to silica gelchromatography, there is obtained the corresponding title compound and,separately, its 15-epimer.

EXAMPLE 32

dl-16,16-Dimethyl-3-oxa-17-methyl-18.19,20-trinor-PGF₂.sub.α and-PGF₂.sub.β Ethyl Esters (Formula XXI: C_(p) H_(2p) is methylene; C_(t)H_(2t) is --C(CH₃)₂ --CH₂ --; R₁ is ethyl; R₂, R₃, R₄, R₅, and R₆ arehydrogen; s is zero, and ˜ is alpha or beta). Refer to Chart A.

Following the procedure of Example 8,dl-16,16-dimethyl-3-oxa-17-phenyl-18,19,20-trinor-PGE₂ ethyl ester(Example 31) is reduced with sodium borohydride to a mixture of thetitle compounds which are separated by silica gel chromatography.

EXAMPLE 33

dl-16,16-Dimethyl-3-oxa-17-phenyl-18,19,20-trinor-PGA₂ Ethyl Ester(Formula XXIX: C_(p) H_(2p) is methylene; C_(t) H_(2t) is --C(CH₃)₂--CH₂ --; R₁ is ethyl; R₂, R₃, R₄, R₅, and R₆ are hydrogen; s is zero;and ˜ is alpha).

Following the procedures of Example 18,dl-16,16-dimethyl-3-oxa-17-phenyl-18,19,20-trinor-PGE₂ ethyl ester(Example 31) is transformed by acid dehydration to the title compound.

EXAMPLE 34

dl-16,16-Dimethyl-3-oxa-17-phenyl-18,19,20-trinor-PGB₂ (Formula XXXVII:C_(p) H_(2p) is methylene; C_(t) H_(2t) is --C(CH₃)₂ --CH₂ --; R₁, R₂,R₃, R₄, R₅, and R₆ are hydrogen; and s is zero).

Following the procedure of Example 20, dl-16,16-dimethyl-3-oxa-17-phenyl-18,19,20-trinor-PGE₂ ethyl ester (Example31) is transformed in basic solution to the title compound.

I claim:
 1. A compound of the formula: ##SPC64##wherein R₁ is hydrogen,alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbonatoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl,phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbonatoms, inclusive, or ethyl substituted in the β-position with 3 chloro,2 or 3 bromo, or 1, 2, or 3 iodo; wherein R₂, R₃, R₄, R₅, and R₆ arehydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein C_(n)H_(2n) is alkylene of one to 10 carbon atoms, inclusive, with one to 5carbon atoms, inclusive, between --CHR₂ -- and --O--; wherein C_(t)H_(2t) represents (1) a valence bond or (2) alkylene of one to 10 carbonatoms, inclusive, substituted with zero, one, or 2 fluoro, with one to 7carbon atoms, inclusive, between --CR₃ OH-- and the ring; wherein T isalkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR₉, wherein R₉ is hydrogen, alkyl of one to 4carbon atoms, inclusive, or tetrahydropyranyl, and s is zero, one, 2, or3, with the proviso that no more than two T are other than alkyl; andwherein ˜ indicates attachment of the group to the ring in alpha or betaconfiguration; including the lower alkanoates thereof, and thepharmacologically acceptable salts thereof when R₁ is hydrogen.
 2. Acompound of the formula: ##SPC65##wherein R₁ is hydrogen, alkyl of oneto 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms,inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenylsubstituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms,inclusive, or ethyl substituted in the β-position with 3 chloro, 2 or 3bromo, or 1, 2, or 3 iodo; wherein R₂, R₃, R₄, R₅, and R₆ are hydrogenor alkyl of one to 4 carbon atoms, inclusive; wherein C_(p) H_(2p) isalkylene of one to 8 carbon atoms, inclusive, with one, 2, or 3 carbonatoms between --CH=CH-- and --O--; wherein C_(t) H_(2t) represents (1) avalence bond or (2) alkylene of one to 10 carbon atoms, inclusive,substituted with zero, one, or 2 fluoro, with one to 7 carbon atoms,inclusive, between --CR₃ OH-- and the ring; wherein T is alkyl of one to4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₉,wherein R₉ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, ortetrahydropyranyl, and s is zero, one, 2, or 3, with the proviso that nomore than two T are other than alkyl; and wherein ˜ indicates attachmentof the group to the ring in alpha or beta configuration; including thelower alkanoates thereof, and the pharmacologically acceptable saltsthereof when R₁ is hydrogen.
 3. A compound of the formula:##SPC66##wherein R₁ is hydrogen, alkyl of one to 8 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2,or 3 chloro or alkyl or one to 4 carbon atoms, inclusive, or ethylsubstituted in the β-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3iodo; wherein R₂, R₃, R₄, R₅, and R₆ are hydrogen or alkyl of one to 4carbon atoms, inclusive; wherein C_(p) H_(2p) is alkylene of one to 8carbon atoms, inclusive, with one, 2, or 3 carbon atoms between--C.tbd.C-- and --O--; wherein C_(t) H_(2t) represents (1) a valencebond or (2) alkylene of one to 10 carbon atoms, inclusive, substitutedwith zero, one, or 2 fluoro, with one to 7 carbon atoms, inclusive,between --CR₃ OH-- and the ring; wherein T is alkyl of one to 4 carbonatoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₉, wherein R₉is hydrogen, alkyl of one to 4 carbon atoms, inclusive, ortetrahydropyranyl, and s is zero, one, 2, or 3, with the proviso that nomore than two T are other than alkyl; and wherein ˜ indicates attachmentof the group to the ring in alpha or beta configuration; including thelower alkanoates thereof, and the pharmacologically acceptable saltsthereof when R₁ is hydrogen.
 4. A compound of the formula:##SPC67##wherein R₁ is hydrogen, alkyl of one to 8 carbon atoms,inclusive, cycloalkyl or 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2,or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethylsubstituted in the β-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3iodo; wherein R₂, R₃, R₄, R₅, and R₆ are hydrogen or alkyl of one to 4carbon atoms, inclusive; wherein C_(n) H_(2n) is alkylene of one to 10carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, between--CHR₂ -- and --O--; wherein C_(t) H_(2t) represents (1) a valence bondor (2) alkylene of one to 10 carbon atoms, inclusive, substituted withzero, one, or 2 fluoro, with one to 7 carbon atoms, inclusive, between--CR₃ OH-- and the ring; wherein T is alkyl of one to 4 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or --OR₉, wherein R₉ ishydrogen, alkyl of one to 4 carbon atoms, inclusive, ortetrahydropyranyl, and s is zero, one, 2, or 3, with the proviso that nomore than two T are other than alkyl; and wherein ˜ indicates attachmentof the group to the ring in alpha or beta configuration; including thelower alkanoates thereof, and the pharmacologically acceptable saltsthereof when R₁ is hydrogen.
 5. A compound according to claim 1 wherein##EQU102##

    --(CH.sub.2).sub.4 --O--CH.sub.2 COOR.sub.1,

wherein R₁ is as defined in claim
 1. 6. A compound according to claim 5wherein C_(t) H_(2t) is straight chain alkylene of one to 4 carbon atomswith or without a fluoro or alkyl substituent on the carbon atomadjacent to the hydroxy-substituted carbon atom.
 7. A compound accordingto claim 6 wherein the side chain hydroxy is in S configuration.
 8. Acompound according to claim 7 wherein R₄ is hydrogen.
 9. A compoundaccording to claim 8 wherein R₃ is hydrogen.
 10. A compound according toclaim 9 wherein C_(t) H_(2t) is (CH₂)_(d) wherein d is one, 2, 3, or 4.11. A compound according to claim 10 wherein d is
 2. 12.3-Oxa-17-phenyl-18,19,20-trinor-PGE₁, a compound according to claim 11.13. 3-Oxa-17-phenyl-18,19,20-trinor-PGE₁, ethyl ester, a compoundaccording to claim
 11. 14. A compound according to claim 8 wherein R₃ ismethyl.
 15. A compound according to claim 14 wherein C_(t) H_(2t) is(CH₂)_(d) wherein d is one, 2, 3, or
 4. 16. A compound according toclaim 15 wherein d is
 2. 17.3-Oxa-15-methyl-17-phenyl-18,19,20-trinor-PGE₁, a compound according toclaim
 16. 18. 3-Oxa-15-methyl-17-phenyl-18,19,20-trinor-PGE₁, ethylester, a compound according to claim
 16. 19. A compound according toclaim 6 wherein the side chain hydroxy is in R (epi) configuration. 20.A compound according to claim 19 wherein R₄ is hydrogen.
 21. A compoundaccording to claim 20 wherein R₃ is methyl.
 22. A compound according toclaim 21 wherein C_(t) H_(2t) is (CH₂)_(d) wherein d is one, 2, 3, or 4.23. A compound according to claim 22 wherein d is
 2. 24.15-Epi-3-oxa-15-methyl-17-phenyl-18,19,20-trinor-PGE₁, a compoundaccording to claim
 23. 25.15-Epi-3-oxa-15-methyl-17-phenyl-18,19,20-trinor-PGE₁, ethyl ester, acompound according to claim
 23. 26. A compound according to claim 2wherein ##EQU103## is

    --CH.sub.2 --CH=CH--CH.sub.2 --O--CH.sub.2 --COOR.sub.1,

wherein R₁ is as defined in claim
 2. 27. A compound according to claim 3wherein ##EQU104## is

    --CH.sub.2 --C.tbd.C--CH.sub.2 --O--CH.sub.2 --COOR.sub.1,

wherein R₁ is as defined in claim
 3. 28. A compound according to claim 4wherein ##EQU105## is

    --(CH.sub.2).sub.4 --O--CH.sub.2 --COOR.sub.1,

wherein R₁ is as defined in claim
 4. 29.dl-3-Oxa-17-phenyl-18,19,20-trinor-PGE₁ ethyl ester, a compoundaccording to claim 1 wherein C_(n) H_(2n) is --(CH₂)₃ --, C_(t) H_(2t)is ethylene, R₁ is ethyl, R₂, R₃, R₄, R₅, and R₆ are hydrogen, s iszero, ˜ represents attachment of the moiety to the ring in alphaconfiguration, and the --OH is attached to the side chain in Sconfiguration.
 30. dl-15-Epi-3-oxa-17-phenyl-18,19,20-trinor-PGE₁ ethylester, a compound according to claim 1 wherein C_(n) H_(2n) is --(CH₂)₃--, C_(t) H_(2t) is ethylene, R₁ is ethyl, R₂, R₃, R₄, R₅, and R₆ arehydrogen, s is zero, ˜ represents attachment of the moiety to the ringin alpha configuration, and the --OH is attached to the side chain in Rconfiguration.